VACTERL Association

Non-random co-occurrence of vertebral, anorectal, cardiac, tracheo-oesophageal, renal and limb anomalies, of heterogeneous aetiology and a diagnosis of exclusion; includes the VACTERL with hydrocephalus subgroup (VACTERL-H) and the monogenic phenocopies that must be excluded, Fanconi anaemia foremost among them.

Literature and regulatory information updated: 17 October 2026.

0. Initial Reference Table

1. Introduction

1.1. Background and founding articles

The combination of polydactyly, imperforate anus and vertebral anomalies was described by Say and Gerald in 1968, in a letter to The Lancet asking whether it was a new syndrome [41]. Killoran and colleagues showed in 2000 that this picture, then called PIV syndrome and also described by Filippi and by Kaufman in 1972, shared with the VATER association central or postaxial polydactyly, short digits, hypoplastic nails, renal anomalies and imperforate anus, and came to regard it as its historical antecedent [1]. Quan and Smith brought together in 1972, in the Birth Defects Original Article Series, and in 1973, in the Journal of Pediatrics, seven patients with vertebral defects, anal atresia, tracheo-oesophageal fistula (TOF) with oesophageal atresia (OA) and radial and renal dysplasia, and coined the acronym VATER as a mnemonic for a co-occurrence that did not appear random [1, 42, 43]. The original patient described by Smith was an infant with vertebral anomalies, anal atresia, OA with TOF, left radial aplasia and hypoplasia of the right thumb, who had normal intelligence at 2 years; the accompanying figure, captioned «VATERR association as initially set forth», shows the frequencies with which each defect occurred when ascertainment started from another (section 10.4) [44].

Shortly afterwards, Nora and Nora (1973 and 1975) and Temtamy and Miller (1974) proposed extending the spectrum to cardiac anomalies and other limb anomalies; Temtamy and Miller compiled 34 cases and spoke of a «VATER syndrome» [2, 43, 45]. A «V» for vascular anomalies, namely single umbilical artery, was also proposed [10]. The acronym evolved into VACTERL: a second «R» (renal) was added, then a «C» (cardiac), and the «L» (limb) replaced the «R» for radial [2]. Later statistical analyses suggested that the evidence for including the cardiac and renal components is weaker than for the others [10].

1.2. Population studies that delimited the entity

Khoury and colleagues, in an American birth defects surveillance registry published in 1983, found 400 cases with two or more components, when only 29 would be expected if the defects occurred by chance, and 76 with three or more, when fewer than one was expected. Of these 76, seven had a recognised cause (five chromosomal and two monogenic) and 19 a recognised phenotype or syndrome of unknown cause; in the remaining 50, considered VACTERL, ventricular septal defect (VSD) was the most frequent heart defect (30%), renal agenesis the most frequent renal anomaly (30%), and reduction defects (34%) and polydactyly (20%) the most frequent limb defects. The authors concluded that VACTERL is a spectrum of combinations that may reflect several recognised disorders and not a single anatomical or aetiological entity [1]. The international study by Botto and colleagues (17 registries of the International Clearinghouse for Birth Defects Monitoring Systems, ICBDMS, about 10 million births between 1983 and 1991) identified 286 newborns with at least three of five VATER components, against 219 expected (p<0.001); 214 (74.8%) had additional defects, and only preaxial limb anomalies were associated with the other components [46]. Källén and colleagues, with 5,260 newborns with multiple malformations from four registries, described a group of OA, anal atresia, preaxial upper limb reduction and costovertebral malformations, subdivided into an «upper» type, associated with heart defects, and a «lower» type, associated with renal anomalies [47].

1.3. The concept of association and reclassifications

An association is a pattern of at least two morphological anomalies that occur together more often than expected by chance, without an identified causal relationship; it is distinguished from a sequence (secondary anomalies cascading from a malformation, disruption, dysplasia or deformation, as in the Robin sequence, in which failure of mandibular growth between the 8th and 11th weeks leads to U-shaped cleft palate and upper airway obstruction), from dysplasia (abnormal cellular or tissue organisation) and from disruption (non-progressive breakdown of a structure with normal developmental potential, such as vascular interruption of a limb) [48]. Smith's defines an association as the non-random tendency of some malformations to occur together more often than chance would lead one to expect, without being components of a syndrome, and states that VACTERL «is not, in itself, a diagnosis» [2]. The Brazilian textbook adds that the developmental disturbance probably occurs early in embryogenesis, affects several organs and has no defined aetiology [49]. Some authors prefer to describe it as a primary polytopic developmental field defect, originating in blastogenesis [10]. The Brazilian textbook Síndromes Genéticas: Reconhecer para Tratar uses «VACTERL sequence» in a caption and a table, a designation that does not correspond to the concept and is not adopted [49]. In 2020, Adam and colleagues regrouped VACTERL with limb-body wall complex (LBWC), MURCS association (Müllerian aplasia, renal aplasia and cervicothoracic somite dysplasia), oculo-auriculo-vertebral spectrum (OAVS), OEIS complex (omphalocele, cloacal exstrophy, imperforate anus and spinal defects) and pentalogy of Cantrell under the name recurrent constellations of embryonic malformations (RCEM), with shared pathogenesis [50]. The overlap of VACTERL with hemifacial microsomia had already been described by Bergmann and colleagues (2003) as axial mesodermal dysplasia complex (AMDC), and the overlap with CHARGE, MURCS and OEIS complex led to the hypothesis of an axial mesodermal dysplasia spectrum; the GeneReviews chapter that brought these data together was retired in 2020 [13].

1.4. VACTERL with hydrocephalus and molecular discovery

Sujansky and Leonard described in 1983 three siblings with VACTERL and hydrocephalus, which suggested recessive inheritance; Briard and colleagues (1984) reported another family, and Evans and colleagues (1989) brought together eight patients with hydrocephalus and at least two other VACTERL anomalies, one of them the child of consanguineous parents, and proposed autosomal recessive and sex-linked forms, with a much worse prognosis than the classic form [3, 51]. Porteous and colleagues (1992) found that two unrelated infants with VACTERL-H had Fanconi anaemia (FA) and proposed chromosome breakage studies in all cases of VACTERL and VACTERL-H [3]. Holden and colleagues (2006) identified, in a three-generation family, a FANCB variant with skipping of exon 7, demonstrating that X-linked FA of complementation group B causes VACTERL-H [52]; McCauley and colleagues (2011) added four families and proposed clinical criteria [20]. In 2010, Wessels and colleagues described a ZIC3 polyalanine expansion in a newborn with heterotaxy and VACTERL [53], and in 2011 Chung and colleagues showed, in a four-generation family with an Xq26.3 deletion, that the same ZIC3 defect can give heterotaxy or VACTERL-H [54]. Exome and genome sequencing, since 2014, has identified mainly monogenic phenocopies and candidate genes of limited evidence, without a major gene for the classic form [55–57]. Since 2024, a DNA methylation episignature common to RCEM has been described, the first biological signature shared by most patients with VACTERL [58].

1.5. OMIM nomenclature and corrections

OMIM numbering has been applied inconsistently in secondary sources. Entry %192350 is the VATER/VACTERL association, of unknown molecular basis; %276950 is VACTERL-H, which includes «VATER association with hydrocephalus» and «VATER association with macrocephaly and ventriculomegaly» (the latter because of the patient with a PTEN variant, in a section of associations pending confirmation («Associations Pending Confirmation»)); #314390 is X-linked VACTERL with or without hydrocephalus (VACTERLX), caused by ZIC3 variants or deletions [1, 3, 6]. The number 300515 corresponds to the FANCB gene and not to a phenotype; FA group B, which may present as X-linked VACTERL-H, is phenotype #300514 [6, 7]. The retired GeneReviews chapter on OA and TOF designates VACTERL-H as «OMIM 300515», which corresponds to the gene and not to the phenotype [12]. In Orphanet, ORPHA:3412 has an exact mapping to OMIM 276950 and is marked as broader than the OMIM 314390 concept, and GeneGuidance associates phenotype #300514 (FA group B) with the same ORPHA:3412, which is consistent with the interpretation that X-linked VACTERL-H corresponds mainly to FA due to FANCB [4, 8]. In ICD-10, VACTERL is an inclusion term under code Q87.2, without its own code, whereas ICD-11 assigns it the specific code LD2F.11 [5]. GeneGuidance associates brachydactyly type D with ORPHA:887, an unfounded mapping that is not used [59]. The OMIM entry corresponding to the HOXD13 variant described in a patient with VACTERL (section 2.8) and that corresponding to the PTEN variant (section 2.6) are now flagged in ClinVar as reclassified, because the contribution of these variants to the VACTERL phenotype has not been confirmed [37].

1.6. Scope and definitions used

This article covers the classic VACTERL association (at least three components without an alternative diagnosis) and, as a subgroup, VACTERL-H. The term «VACTERL-like» designates patients with two components, a criterion used in several research cohorts [55, 60]. Monogenic and chromosomal causes that reproduce the phenotype are treated as phenocopies that require the diagnosis to be reclassified: FA, PTEN hamartoma tumour syndrome (with evidence from a single patient for the VACTERL phenotype), CHARGE syndrome, 22q11.2 deletion and heterotaxy due to ZIC3.

2. Molecular Genetics and Pathophysiology

2.1. Aetiological heterogeneity and the current model

VACTERL is clinically and aetiologically heterogeneous and, in most cases, has no identified cause; it generally occurs sporadically in a family without a prior history [2, 61]. Solomon's 2018 review describes it as possibly a «group of conditions» with different mechanisms converging on a similar phenotype [61]. The accepted model is multifactorial: a minority of patients have a monogenic or chromosomal phenocopy that, once identified, removes the patient from the association category; another group will have low-effect genetic contributions, inherited copy number variants (CNVs) or maternal factors; and a fraction may result from early embryonic disruption without a germline genetic component [10, 55, 62]. In the German trio-exome study by Ćomić and colleagues (2025), no inherited variant proved causal and case-control gene burden tests did not reach significance, reinforcing the hypothesis that the classic form is rarely Mendelian [55].

2.2. Embryonic mechanisms

The synchrony of the components places the defect in blastogenesis, when the notochord, somites, primitive gut, mesonephros and limb buds form [2, 10]. The time windows of the components coincide: TOF results from incomplete division of the cranial portion of the foregut into respiratory and oesophageal parts between days 23 and 28 after conception [63]; the upper limb bud forms on days 26–27 after fertilisation and the limb is complete by about day 55, and environmental factors acting in this interval cause defects of variable severity, whereas genetic syndromes tend to give bilateral defects with less difference between sides [64]; most ARMs result from abnormal development of the urorectal septum, with incomplete separation of the cloaca into urogenital and anorectal portions [65]. The Sonic hedgehog (SHH) pathway has been implicated by animal models: mice with defects in Shh signalling and in the Gli transcription factors develop a spectrum of anomalies similar to VACTERL, and Kim and colleagues proposed them as a model [1, 10]. In humans, however, loss of function of SHH causes holoprosencephaly, so isolated VACTERL does not have SHH variants; FOXF1, linked to the SHH pathway, gives a VACTERL-like phenotype, and HOXD13 is a downstream target; the Hox and retinoic acid pathways are also invoked [10]. Hilger and colleagues showed expression of Zic3 in the limbs and prevertebral structures and of Foxf1 in the oesophagus, trachea, vertebrae, anus and genital tubercle of mouse embryos between E9.5 and E14.5 [66]. A 2026 review proposes transient hypoxia followed by reoxygenation, with production of reactive oxygen species (ROS), as a mechanism common to RCEM, based on animal models of hypoxia, cocaine and nicotinamide adenine dinucleotide (NAD) deficiency and on 38 of 44 reports (86%) of multiple malformations consistent with the RCEM spectrum after hormonal pregnancy tests (HPTs, such as Primodos®), in which VACTERL was the most frequent constellation; the authors present it as a hypothesis and not as proof of causation [62].

2.3. Fanconi anaemia as a cause of the VACTERL and VACTERL-H phenotype

FA is the monogenic phenocopy with the greatest clinical impact, because of the bone marrow failure and cancer risk that accompany it. In a European study, 5% (13/245) of patients with FA had a VACTERL phenotype; all had radial ray anomalies and 12 of the 13 had at least one other sign of FA (café-au-lait spots, growth retardation, microcephaly or dysmorphism), with over-representation of the FANCD1, FANCE and FANCF groups [2, 67]. GeneReviews records the VACTERL-H phenotype in 12% of individuals with FA and the PHENOS phenotype (pigmentation, small head, small eyes, central nervous system, otological abnormalities and short stature) in 9% [14]. The clinical guidelines of the Fanconi Anemia Research Fund (FARF, 5th edition, diagnosis chapter revised in 2026) define VACTERL-H as the presence of at least three of eight components (vertebral, anal, cardiac, TOF, oesophageal or duodenal atresia, renal, upper limb and hydrocephalus) and estimate that 5–30% of patients with FA meet this criterion, the combination of renal and limb anomalies being the most suggestive of FA [11]. In the Portuguese national FA cohort (cytogenetics laboratory of the Faculty of Medicine of the University of Porto, 93 cases diagnosed between 1993 and 2025), VACTERL-H was present in 6 of 93 patients (7%), with an upper limb anomaly in 28%, heart defect in 14%, renal anomaly in 12%, oesophageal or duodenal atresia in 9%, anal atresia in 7%, vertebral defect in 2%, TOF in 1% and no hydrocephalus; 45 of the 50 patients with molecular confirmation had FANCA variants, and the authors attribute the low proportion of VACTERL-H to the predominance of this genotype [68]. Smith's states that, in FA, the VACTERL phenotype is more associated with the BRCA2 group [9]. The common mechanism is a defect of the FA core nuclear complex, a ubiquitin ligase that monoubiquitinates FANCD2 and FANCI: without it, interstrand DNA crosslinks persist, replication forks collapse and breaks and radial figures appear, and the same defect explains the bone marrow failure, the embryonic malformations and the cancer predisposition [8]. Alter and Rosenberg's review of 2,245 published cases (1927–2012) found 108 patients with at least three VATER features, of whom only 29 had been recognised as such by the authors; in these patients, the combination of renal and limb (radial or thumb) anomalies was present in 93%, versus less than 30% in VATER without FA, and genotypes were distributed among FANCA (19%), FANCB (21%), FANCD1/BRCA2 (14%) and FANCD2 (12%), with shorter median survival and earlier neoplasms [29]. Fiesco-Roa and colleagues, in 1,101 cases with a known gene, associated biallelic or hemizygous null variants with more anomalies, renal malformations, microcephaly, short stature and VACTERL-H than hypomorphic genotypes, and stressed that the absence of VACTERL-H does not exclude FA [69].

FANCB (Xp22.2; OMIM gene *300515; MANE transcript NM_001018113.3) accounts for about 2% of FA and is also essential for spermatogenesis, so it is associated with male infertility [8, 14]; about 70% of variants are detected by sequencing and about 30% by deletion and duplication analysis [8, 70]. About 80% of boys with truncating or null FANCB variants have VACTERL-H, the highest rate of congenital anomalies in FA, and a further 5% or so have PHENOS; truncating variants are more severe than missense variants, and the haematological phenotype is mainly early bone marrow failure [14]. FARF describes a milder phenotype with missense variants or with somatic mosaicism [11]. Female carriers have highly skewed X inactivation in blood and are not detectable by the DEB or mitomycin C (MMC) breakage test [8, 20, 52]. In the Holden family, the FANCB variant was a G>A substitution at position +5 of the intron 7 splice donor (historical notation IVS7DS+5G-A in OMIM), now normalised as NM_001018113.3:c.1496+5G>A, which causes skipping of exon 7 and a premature termination codon, classified as pathogenic in ClinVar (VCV000010870, no assertion criteria); the female carriers in the family had 100% skewed X inactivation [37, 52, 70]. McCauley described, among others, the variants 2150T-G (L717X) and 1857delAG, in historical notation without a stated transcript [7]. In McCauley's four families, all variants were truncating; of the 12 patients, the major signs were ventriculomegaly, bilateral absence of thumbs and radii, vertebral defects, renal agenesis and growth retardation, and the less frequent ones brain, pituitary, ear and eye malformations, digestive atresias, TOF, lung segmentation defects and small genitalia; three of six survived the perinatal period, and one boy lived to 2 years and 10 months, developed aplastic anaemia and died of renal failure [20].

Other FA genes produce VACTERL phenotypes. Alter and colleagues found three or more VATER anomalies in 5 of 27 patients with FA group D1 due to biallelic BRCA2 variants, one of them with VACTERL-H, and the VATER phenotype has been described in groups A, C, E, F and G [1, 9]. Truncating FANCL variants in two families produced a severe VACTERL phenotype with early postnatal death [71]; of the 16 cases of FA due to FANCI published up to 2016, 7 (44%) had at least three VACTERL features [72]. RAD51 causes an autosomal dominant de novo form (group FANCR): Altintas and colleagues described a 10-year-old girl with VACTERL anomalies, duodenal atresia and PHENOS, a likely pathogenic de novo variant and an inconclusive breakage study, in an article describing a strong association of RAD51 with VACTERL [14, 73].

2.4. ZIC3 and X-linked VACTERL

ZIC3 (Xq26.3; OMIM gene 300265; MANE transcript NM_003413.4) encodes a C2H2 zinc finger transcription factor required for specification of the left-right axis and the axial midline, in the primitive streak and the node [30, 70]. Its variants cause X-linked visceral heterotaxy (HTX1, OMIM 306955), non-syndromic congenital heart disease and VACTERLX (#314390); they account for about 1% of sporadic heterotaxy, and all known genes together account for less than 20% of laterality defects [6, 30]. The X-linked VACTERL phenotype due to ZIC3 includes vertebral anomalies, anal atresia, heart defects, TOF, renal anomalies (such as urethral atresia with hydronephrosis) and limb anomalies (hexadactyly, humeral hypoplasia, radial aplasia and proximally placed thumb), sometimes with hydrocephalus [30]. Wessels and colleagues identified, in a newborn with anal atresia, laryngeal and oesophageal atresia with TOF, cardiac dextroposition with a persistent left superior vena cava and a unilateral multicystic kidney, who died one hour after birth, a 6-nucleotide in frame insertion in the GCC repeat of exon 1, which increases the N-terminal polyalanine tract from 10 to 12 residues; the insertion was absent in the mother and in 336 control chromosomes [6, 53]. In current nomenclature, it corresponds to NM_003413.4:c.165_166insGCCGCC p.(Ala54_Ala55dup), classified as pathogenic in ClinVar (VCV000029955, OMIM submission without assertion criteria) [37, 70]. Heterozygous females are not reliably unaffected: in Gebbia's original report (1997) some had situs inversus, and the spectrum includes affected women, probably due to variable X inactivation, which justifies echocardiography and abdominal imaging in heterozygous females [30]. In the four-generation Italian family of Chung and colleagues, a deletion of about 1.3–1.4 Mb at Xq26.3 including ZIC3 produced classic heterotaxy in a fetus, imperforate anus in a maternal great-uncle and in a brother, and VACTERL-H without heterotaxy in another brother, with six asymptomatic female carriers [6, 54]. ZIC3-related laterality disorders may include atresias of the oesophagus, duodenum and anus and cardiac, biliary and renal malformations, and digestive atresias are possibly an underestimated component [74]. The Oxford Desk Reference describes the X-linked ZIC3 laterality sequence, in which the laterality disorder may combine with sacral agenesis or neural tube defects, and recommends ZIC3 analysis when the pedigree suggests X-linked inheritance [75, 76]; Smith's states that ZIC3 variants are frequently associated with hindgut anomalies [77]. The cytobands given in these books (Xq28 in the Oxford, Xq26.2 in Smith's) do not match the current location at Xq26.3 [30]. The birth prevalence of heterotaxy of all causes was 1.18 per 10,000 live births in the Texas registry (1999–2006), with first-year mortality of 30.9%, a figure that does not measure the frequency of ZIC3-related disease [30]. The clinical approach to heterotaxy includes assessment of splenic anatomy and function, a search for Howell-Jolly bodies, infection prevention, echocardiography and an upper gastrointestinal contrast study for rotation anomalies [30].

2.5. FOXF1 and the 16q24.1 region

FOXF1 (16q24.1; OMIM 601089; MANE transcript NM_001451.3) causes, through haploinsufficiency, ACDMPV (OMIM 265380; ORPHA:210122), usually lethal in the neonatal period; about 90% of cases result from a deletion or point variant of FOXF1 or of its upstream enhancer, so a normal coding sequence does not exclude the disease [31, 70]. About 80% of patients have extrapulmonary malformations: digestive (malrotation, atresias), cardiovascular (hypoplastic left heart) and genitourinary; point variants are associated mainly with malrotation and microdeletions with hypoplastic left heart and digestive atresias, through additional haploinsufficiency of FOXC2 and FOXL1 [31, 32]. About 60% of point variants lie in the DNA-binding domain; deletions of the long-range enhancer suppress expression through a position effect, and the missense allele S52F acts by inhibiting STAT3 signalling and not by simple loss of protein, so chromosomal microarray is needed alongside sequencing [31]. ACD, as a clinicopathological entity, has a birth prevalence of 1.2 per 100,000 in Canada according to Orphanet, a figure that is probably an underestimate because the diagnosis is often post mortem [31]. In 165 patients published between 2018 and 2025, mean survival without lung transplantation was about 7 months [31]. Stankiewicz and colleagues described six overlapping microdeletions of the FOX cluster at 16q24.1q24.2, four heterozygous FOXF1 variants (frameshift, nonsense and no-stop) and upstream deletions with a position effect, generated by Alu microhomology-mediated replication mechanisms [32]. Hilger and colleagues found the variant NM_001451.3:c.658G>T p.(Gly220Cys) de novo in a boy with anorectal malformation (ARM), left renal agenesis and glandular hypospadias; in ClinVar it is classified as likely pathogenic by a single submitter (2015) [37, 66].

2.6. PTEN: evidence from a single patient

Reardon and colleagues described in 2001 a heterozygous de novo PTEN variant, H61D (p.(His61Asp); OMIM 601728.0030), in a child with macrocephaly, ventriculomegaly, TOF and bilateral radial hand anomalies; the authors acknowledged that the patient was not a classic example of the phenotype [3, 36]. The variant is normalised as NM_000314.8:c.181C>G p.(His61Asp) and is classified in ClinVar as likely pathogenic by a ClinGen expert panel (assessment of 18 March 2026), a classification that refers to PTEN hamartoma tumour syndrome; the OMIM entry «VATER association with macrocephaly and ventriculomegaly» appears in the same record as reclassified, because the contribution of the variant to the VACTERL phenotype has not been confirmed [37, 70]. OMIM places this observation in the section of associations pending confirmation («Associations Pending Confirmation»), and the PanelApp VACTERL panel rates PTEN red (insufficient evidence) [3, 78]. In practice, macrocephaly in a patient with VACTERL components is a clue to PTEN hamartoma tumour syndrome and not a demonstration that PTEN causes VACTERL.

2.7. TRAP1 and reclassification of the original variants

TRAP1 (16p13.3; OMIM 606219; MANE transcript NM_016292.3) encodes a mitochondrial chaperone of the HSP90 family [70, 79]. Saisawat and colleagues described in 2014 recessive variants in five families, two with isolated congenital anomalies of the kidney and urinary tract (CAKUT) and three with VACTERL, after screening 675 patients with CAKUT and 300 with classic VACTERL [80]. The Central European family A4252 was homozygous for p.(Arg469His) through partial maternal isodisomy; the Dutch family A4884 was compound heterozygous for c.757A>G p.(Ile253Val) and c.1573C>T p.(Leu525Phe); family EA1717 had c.1330T>A p.(Tyr444Asn) and c.1663G>A p.(Val555Ile) [80]. The p.(Arg469His) variant had an allele frequency of 0.9% in Americans of European ancestry and was proposed as a European founder variant [80]. At the October 2026 consultation, the variants NM_016292.3:c.1406G>A p.(Arg469His) and c.757A>G p.(Ile253Val) were classified in ClinVar as benign or likely benign by several submitters, without conflicts [37]. Kolvenbach and colleagues (2021) state that earlier large-scale resequencing studies confirmed only TRAP1 and ZIC3 among the proposed genes; in their own exome study of 21 individuals and families with VATER/VACTERL and a renal phenotype, they found potentially pathogenic biallelic or hemizygous variants in 6 (29%), in the genes B9D1, FREM1, ZNF157, SP8, ACOT9 and TTLL11 [56]. Trap1 is expressed in the renal epithelium of the developing mouse kidney and in the proximal tubules and thick ascending limbs of the adult rat [79]. PanelApp rates TRAP1 green (autosomal recessive) and GenCC records a single «strong» submission; OMIM and ClinGen record no gene-disease relationship [78, 79]. TRAP1 should be treated as a candidate gene, and the original variants are not presented as causal.

2.8. Other genes and subgroups

Other genes that appear in research lists (LPP, SHH, PCSK5, ESR2) have no curated relationship with VACTERL in GeneGuidance: LPP has no germline disease, SHH causes holoprosencephaly 3, PCSK5 has no clinical curation and ESR2 is associated with ovarian dysgenesis [98–101]. In the FGF10 case, OA and pulmonary hypoplasia were present only in the proband, and the authors postulate a second hit [89].

The mitochondrial hypothesis began with Damian and colleagues (1996): an infant with VACTERL, who died at 1 month of renal failure, had 100% mitochondrial DNA with the m.3243A>G variant in the multicystic renal tissue and 32% in normal tissue, and the mother and sister later developed a classic mitochondrial cytopathy [1]. Stone and Biesecker (1997) did not detect the variant in 62 patients with VACTERL, although they studied only lymphocytes, and suggested that Damian's patient may have had oculo-auriculo-vertebral dysplasia [1]. In the Ćomić cohort, a child with coccygeal agenesis, ARM with perineal fistula and OA with TOF had m.3243A>G with 13% heteroplasmy (3% in the mother), without mitochondrial signs, with uncertain causality [55]. Signs of mitochondrial disease may appear long after the neonatal period [10].

2.9. Chromosomal anomalies and CNVs

Chromosomal anomalies are present in about 6–10% of children with OA/TOF, including trisomy 21 (about 0.5–1.0%), trisomy 18, trisomy 13 and trisomy X [12]. The 13q34-qter and 22q11 deletions are associated with OA/TOF with VACTERL findings, and the distal 13q deletion includes VACTERL among its occasional anomalies; VACTERL within a broader pattern, such as trisomy 18 or del(13q), has an unfavourable prognosis [2, 12, 102]. The 16q24.1 and 2q31.1 microdeletions may also give a VATER/VACTERL phenotype [65]. In the review by Felix and colleagues (2007), cited by GeneReviews, recurrent CNVs in OA/TOF included duplications of 3p25-pter and 5q34-qter and deletions of 2q37.2-qter, 4q35-qter, 5p15-pter, 6q13-q15, 14q32.3-qter and 17q22-q23, and Brosens and colleagues (2014) found rare CNVs containing genes, some de novo, in both isolated and non-isolated OA/TOF [12]; interstitial 17q deletion is rare [63]. High-density microarray (more than 1 million single-nucleotide polymorphisms, SNPs) in more than 100 well-phenotyped patients found likely pathogenic de novo aberrations in 3–5% [43]. Zhang and colleagues found, in 115 VATER/VACTERL and VACTERL-like patients, 20 rare CNVs absent from 1,307 controls, but only two causal (2%; one de novo 17q12 and one 22q11.21), and 15 were inherited from a healthy parent [60]. Brosens and colleagues found no de novo CNVs larger than 30 kb in 68 patients from Rotterdam and described recurrent inherited rare CNVs, interpreted as possible modifiers [103]. A de novo deletion of about 7.7 Mb at 7p15.3-p21.2, including TWIST1, explained a case with coronal synostosis and intellectual disability in the Ćomić trio-exome study [55].

2.10. Normalisation of the variants cited

The table uses MANE Select transcripts confirmed in VariantValidator [70]. Saisawat's article used version NM_016292.2 of the TRAP1 transcript, and Hilger's NM_003413.3 of ZIC3 and NM_001451.2 of FOXF1; the c. numbering of the variants is unchanged in the MANE versions [66, 70, 80]. In the ZIC3 polyalanine tract, ClinVar records other variations with different numbering anchors (for example c.135CGC[12] p.(Ala55_Phe56insAlaAlaAla), of uncertain significance, and c.135CGC[8] p.(Ala55del), with conflicting classifications), so equivalence between repeat notations is established only in VariantValidator and not manually [37, 70]. The HOXD13 variant should not be confused with c.183_203del p.(Ala65_Ala71del), which is pathogenic and unrelated to the VACTERL case [37]. The SALL1, SALL4 and MID1 variants of van de Putte, the HAAO and KYNU variants of Shi, the PACS2 variant of Massey, the MED14 variant of Liu, the WBP11 variants of Ma and the FGF10 variant of Escalante-Reyes have no transcript stated or verified in the extracted texts and were not normalised, and the FOXF1 deletions of Stankiewicz have no per-patient coordinates in the sources consulted [32, 57, 82, 88, 89, 93, 95]. ZIC3 p.(Gly17Cys), found by Hilger in four patients (including siblings, inherited from an unaffected mother in one case), should not be used as an example of a causal variant [37, 66].

2.11. Maternal and environmental factors and twinning

Pregestational maternal diabetes is the best-supported maternal factor. In the study by Bell and colleagues (more than 400,000 pregnancies, 1,677 of diabetic mothers), the risk of major non-chromosomal malformation was 7% (relative risk, RR, 4), rose from 1 in 33 with a periconceptional glycated haemoglobin (HbA1c) of 6.1% to 1 in 9 with HbA1c of 10%, and increased by about 30% for each 1% above 6.3%, with no difference between type 1 and type 2 diabetes and no increase in gestational diabetes; the RR of VATER/VACTERL was increased, although most cases occur, in absolute numbers, in children of non-diabetic mothers [104]. Castori and colleagues described an obese, diabetic woman with one pregnancy with sirenomelia, one miscarriage and one termination with VACTERL confirmed at post mortem examination, and proposed that the two entities are extremes of the same spectrum [105]. Infertility treatments, exposure to oestrogens and progestogens, statins and lead have also been mentioned, associations that require cautious interpretation [10], as well as pre-pregnancy overweight or obesity and maternal smoking [55].

In the prospective cohort of Tark and colleagues (2026), with 1,555,936 live births from four US states between 2004 and 2018, the prevalence of VACTERL was 1.2 per 10,000 (95% CI 1.0–1.4) with natural conception and 2.3 per 10,000 (1.7–3.2) after in vitro fertilisation (IVF), with an adjusted odds ratio (aOR) of 1.86 (1.16–2.98), without variation with intracytoplasmic sperm injection (ICSI), fresh or frozen embryo transfer or male infertility; the authors stress that the absolute risk is low [16]. The result agrees with data from 28 EUROCAT registries (aOR 1.9; 0.9–4.0) and from the Netherlands (aOR 4.4; 2.1–8.8) [16]. In a different direction, in the European Paediatric Surgeons' Association (EUPSA) registry of 374 patients with OA, VACTERL was 25.0% after medically assisted reproduction (MAR) and 18.5% after natural conception (p=0.398) [106]. Radial ray teratogens include thalidomide, carbamazepine, alcohol, vitamin A and diabetic embryopathy, and carbimazole and methimazole increase the risk of OA/TOF [107, 108]. In maternal diabetes, the risk is limited to women who are diabetic at the time of conception, applies to type 1 and type 2 diabetes, and the proposed mechanism involves simultaneous changes in inositol, prostaglandin and reactive oxygen species metabolism; hypoglycaemia is teratogenic in animal models, but is not established as a human teratogen [104].

VACTERL is among the early defects in excess in monozygotic twins, with concordance in only 5–20% of pairs [109]. In the review of twins with RCEM, phenotypic discordance was 80% and 18.5% of pregnancies resulted from MAR [50]. In Tark's American cohort, 6.3% of children with VACTERL were from twin pregnancies, versus 3.2% of children without defects [110]. These data support the hypothesis of post-zygotic embryonic disruption in some cases [62].

2.12. Methylation episignature

Haghshenas and colleagues studied DNA methylation in peripheral blood from 53 individuals with RCEM (VACTERL and/or OAVS) and found a common episignature in 40, with which they developed a sensitive and specific binary classifier [58]. An independent Canadian validation, published as a preprint without peer review in July 2026, found a robust signal in 18 of 21 patients with VACTERL (85.7%) and an intermediate signal in the other three, with variable results in other RCEM, and the authors interpret the variable detection as a sign of aetiological heterogeneity [111]. A 2026 report described a moderately positive RCEM episignature in an infant with a Moebius-plus phenotype [112]. The episignature does not identify a cause, but suggests an epigenetic or exposure mechanism common to RCEM.

2.13. Penetrance, expressivity and sex

Monogenic forms have variable expressivity: in Chung's ZIC3 family, the same deletion gave heterotaxy, isolated imperforate anus and VACTERL-H [54]; in the RPL18 family, carriers had anything from a single defect to multiple defects [96]. Some studies suggest an excess of male patients, explained by hypotheses such as X linkage, sex-influenced expression or imprinting [10]: there were 57.0% boys in Tark's oncology cohort and 64.0% in the IVF cohort, but 55% girls in the National Institutes of Health (NIH) cohort of 60 patients, without a significant difference [16, 110, 113]. In the EUROCAT series of 397 cases, 65% were male; major ARM was more frequent in boys (65% versus 56%, p=0.06) and major heart defect in girls (65% versus 54%, p=0.03) [17]. In FANCB carriers, skewed X inactivation explains the absence of phenotype [20, 52].

3. Clinical Spectrum and Manifestations by System

3.1. Frequency of components and ascertainment bias

The frequency of each component depends on how patients were ascertained: birth defect registries include severely affected fetuses and newborns, without FA testing or microarray, and tend to overestimate; genetics clinics see mainly less severely affected survivors and tend to underestimate [10]. Most children have three or four components [65].

Sources: [2, 10, 16, 17, 55, 113]. The German cohort was recruited with the support of ARM and tracheo-oesophageal malformation patient associations, which explains ARM in 97% of cases [55]. In the American population-based cohort, the most frequent combination was cardiac-renal-anal (20.5%), whereas on other continents the vertebral-anal, anal-renal or vertebral-oesophageal-anal combinations predominate [16]. In the eight-state American oncology cohort, TOF was present in only 25% of cases, a difference attributed to registry criteria and ascertainment [110]. In the NIH cohort, no pair of components was significantly associated when considered in isolation; latent class analysis suggested five subgroups (38%, 26%, 20%, 12% and 4%), with separation between upper and lower gastrointestinal tract malformations, and only the vertebral-cardiac-renal cluster had 90% support in hierarchical clustering, findings that the authors consider in need of replication [113]. The Brazilian textbook presents, in a six-row table, frequencies without a denominator or primary source that coincide with the ranges of Solomon 2011: vertebral anomalies 60–80%, anal atresia 55–90%, cardiac malformations 40–80%, TOF with or without OA 50–80%, renal anomalies 50–80% and limb anomalies 40–50% [49].

The EUROCAT study by van de Putte and colleagues (2020b) analysed 501 cases coded as VACTERL in 29 population-based registries from 16 European countries, including Portugal, born between 1980 and 2015, after excluding 21 cases of VACTERL-H and 13 with explanatory syndromes (Fanconi anaemia, caudal regression, Goldenhar, sirenomelia, 22q11 deletion) [17]. Of the 501, 397 (79%) met the criteria: 213 (54%) strict VACTERL (at least three major components, without additional major anomalies), 82 (20%) «VACTERL-like» (fewer than three major components, but at least three counting minor ones, or ARM with OA/TOF only) and 102 (26%) «VACTERL-plus» (with a major anomaly outside the spectrum, mainly digestive, such as duodenal atresia or malrotation) [17]. Ninety per cent had ARM and/or OA/TOF (ARM only 28%, OA/TOF only 28%, both 34%); 69% had at least three major components (triad 49%, tetrad 15%, pentad 4%, the complete spectrum in a single case), and exploratory factor analysis identified no natural clusters of three or more components [17]. Genitourinary anomalies were present in 16%, respiratory anomalies in 11% and lower limb anomalies in 13%, and tethered cord in 9 patients, all with ARM [17]. Only 16 of the 29 registries performed genetic testing to exclude alternatives, and the authors propose that the «plus» subgroup be prioritised for genetic testing and that strict VACTERL be the group of choice for aetiological studies; they do not support adding «GU» to the acronym [17].

The diagram in Figure 1C of the Smith's chapter, based on the initial series of Quan and Smith (1973) and without denominators, shows the frequency of the target defect when the patient is ascertained through another defect: from TOF, vertebral defects in 23%, imperforate anus in 10% and radial dysplasia in 7%; from imperforate anus, vertebral defects in 36%, TOF in 7% and radial dysplasia in 5%; from radial dysplasia, vertebral defects in 27%, TOF in 3% and imperforate anus in 3% [44].

3.2. Vertebral component

Vertebral anomalies are present in 60–95% of patients, depending on the series [19, 114]. They include hemivertebrae, butterfly or wedge vertebrae, fusions, and supernumerary or absent vertebrae, and are accompanied by rib anomalies; abnormal ribs may exist without a vertebral defect, and scoliosis may be the first sign [10, 49]. They predominate in the upper and mid-thoracic spine and in the lumbar spine [65]. Isolated sacral dysplasia in a patient with ARM is a component whose inclusion is controversial [10]. Occult spinal dysraphism with tethered cord is frequent, especially with ARM or urogenital anomalies, and may be accompanied by a lipoma of the filum or conus, ependymal cysts, myelomeningocele and syringohydromyelia [2, 19]. In a series of ARM studied by lumbosacral magnetic resonance imaging (MRI), there were anomalies in 30% of low forms and 50% of high forms [65]; the eUROGEN guideline estimates tethered cord or other spinal cord anomalies in 10–60% of patients with ARM [115]. In the Kansas City series of 112 patients with OA, 24.1% had vertebral anomalies, and in the screened Amsterdam OA cohort, 32% [116, 117]. In the EUROCAT series, only anomalies of non-sacral vertebrae counted as a major component, and sacral anomalies as minor [17]. Congenital scoliosis due to vertebral malformation requires classification, assessment of the risk of progression and consideration of surgical options in the young child.

3.3. Anorectal and genital component

ARM ranges from imperforate anus with or without fistula to persistent cloaca; stenoses may appear normal on inspection and present late with obstruction [10, 19]. An abdominal mass in a female newborn may be hydrocolpos [19]. In 105 patients from the NIH cohort (89 meeting strict criteria), genital anomalies occurred in 21%, were more severe (though not more frequent) in females and also occurred without renal, lower vertebral or lower gastrointestinal tract malformations [118]. Anal anomalies occur in about 4 per 10,000 births; only one third are isolated and two thirds are accompanied by other anomalies; among isolated anomalies, 75% are atresias (10% high, above the levator ani muscle, and 90% low), with male predominance (ratio 6.7 in high and 2.3 in low forms), followed by congenital anal fistula (15%), ectopic anus (3%) and persistent cloaca (1%); anal atresia or stenosis is a feature of 135 syndromes in the London Dysmorphology Database [65]. In ARM series, associated anomalies are genitourinary in 49% and cardiovascular in 27% [65]. In the Swedish cohort of 93 children operated on for OA (Lund, 2012–2023), genital malformations occurred in 12.9% and urinary malformations in 19.4%, but, in the 31 with VACTERL, in 29% (9/31) and 51.6% (16/31), with more UTIs, neurogenic bladder and intermittent catheterisation, and half of those affected needed additional urogenital surgery [119]. In the eUROGEN guideline, a systematic review estimated sexual dysfunction in 50% of women and erectile dysfunction in 12% of men with ARM, and the overall birth rate is around 20%, excluding cloaca [115]. The Finnish population cohort of ARM (2004–2017) recorded a total prevalence of 8.00 per 10,000 births and an association of VACTERL with neonatal and infant mortality [120].

3.4. Cardiac component

Heart defects occur in 40–80% [10]. In the NIH cohort with echocardiography, 31 of 46 patients (67%) had congenital heart disease, VSD being the most common (18/31, 58%); the severity of the heart defect was not associated with the presence of ARM (p=0.18) or TOF (p=0.72) [121]. The Brazilian textbook lists VSD, PDA, ASD and right aortic arch [49]. Isolated PDA and patent foramen ovale (PFO) do not count as a component [10, 110]. In the Amsterdam cohort of 281 patients with ARM, 241 underwent echocardiography and 80 (33.2%) had a heart defect, mainly ASD (36), VSD (29) and persistent left superior vena cava (17); VACTERL and genetic syndromes were independently associated with heart disease, and the proportion diagnosed remained stable (30.2%, 34.5% and 34.0%) while screening increased from 74.1% to 95.9% [122]. In an Egyptian cohort of 314 ARMs (2013–2022), 92 (29.3%; 95% CI 24.3–34.7%) had a heart defect, significant in 48, mainly ASD (28.3%), VSD (26.1%) and tetralogy of Fallot (10.9%); heart disease was more frequent in complex ARM (52.9% versus 23.1%), and the presence of at least two VACTERL components was associated with heart disease (odds ratio, OR, 4.8; 95% CI 2.9–8.1) [123]; in an Iranian series of 57 ARMs, associated anomalies were cardiovascular in 52.6%, genitourinary in 36.8% and vertebral in 24.6% [124]. Supraventricular and ventricular arrhythmias may occur, and conduction disease, typical of Holt-Oram syndrome, has also been described in VACTERL [10, 19].

3.5. Tracheo-oesophageal and respiratory component

OA with or without TOF occurs in 50–80% and manifests with polyhydramnios, absence of the gastric bubble and inability to pass a nasogastric tube [10]. About 80% of OAs have an associated TOF [63]. The configurations described by Clark (1999) and reproduced by GeneReviews are OA with distal TOF (84%), isolated OA without TOF (8%), H-type TOF without OA (4%), OA with proximal and distal TOF (3%) and OA with proximal TOF (1%) [12]. TOF occurs in about 1 in 3,000 live births, with a slight male predominance; in more than 85% it is associated with OA, about 50% of patients have another major malformation, and only about 45% of TOFs are isolated anomalies [63]. Among probands with OA/TOF, 40% have the isolated form and 60% the non-isolated form, about 10% with a specific syndromic diagnosis and about 10% with the VACTERL association [12]. At neonatal presentation there are copious oral secretions, coughing, choking, cyanosis, vomiting and respiratory distress [12]. In a Japanese series of 37 OAs (2000–2025), 11 (29.7%) had VACTERL, and long-gap OA was more frequent with VACTERL (54.5% versus 19.2%), with later oesophageal reconstruction (mean age 208.5 versus 47.2 days) [125]. In a Spanish cohort of 105 newborns with OA (Valencia, 2005–2024), 44.8% had associated anomalies, mainly cardiac, and prenatal diagnosis was made in 10.5% [126]. H-type TOF, without atresia, has a normal tube passage and gastric bubble and presents with choking and respiratory distress with feeds [19]. Even without a true TOF, there may be swallowing and breathing abnormalities [10]. Laryngeal stenosis, bronchial anomalies and tracheomalacia are part of the spectrum [2]; Hattori and colleagues described an 11-month-old boy with recurrent wheezing and right upper lobe atelectasis due to an ectopic bronchus, without TOF, whose diagnosis rested on vertebral and rib anomalies, imperforate anus with perineal fistula, unilateral hydronephrosis, ASD and a preauricular tag [1]. In the Kansas City OA series, 32.1% had cardiac anomalies, 17.0% urinary and 16.1% skeletal anomalies [116]. About 50% of children with OA have at least one other digestive anomaly, usually within VACTERL; malrotation occurs in 8.6–12.7% and hypertrophic pyloric stenosis in about 7.5% [127]. Vascular anomalies (aberrant right subclavian artery in 12% and right aortic arch in 6% in a series of 76 children) may cause dysphagia or dyspnoea through compression [127]. Heterotopic gastric mucosa occurs in up to 34% and gastric heterotopic pancreas in 18.7% (versus 0.5% in controls), and the diagnosis of hypertrophic pyloric stenosis is often delayed (median 6 days) [127]. Respiratory symptoms are frequent: cough in 8–75%, wheeze in 14–40%, recurrent infections in 10–53%, tracheomalacia in 14–29%, bronchiectasis in up to 17%, and restrictive functional abnormalities in 11–69% and obstructive abnormalities in 38–50% [127]. The respiratory recommendations of Koumbourlis and colleagues (2020) identify tracheomalacia at the fistula site as the anomaly that predisposes to respiratory complications and aspiration due to altered protective reflexes as the main contributing mechanism [128].

3.6. Renal and urinary tract component

Renal anomalies occur in 50–80% and include unilateral or bilateral agenesis, horseshoe kidney and cystic or dysplastic kidneys, which may go unnoticed without imaging [10, 49]. In the NIH cohort with ultrasound, 33 of 48 patients (69%) had a renal manifestation: vesicoureteric reflux (VUR) with a structural defect in 27%, unilateral renal agenesis in 24%, dysplastic or multicystic kidneys in 18% and a duplex collecting system in 18%; 22 of the 25 patients (88%) with a structural renal anomaly had ARM [129]. Urolithiasis and urinary tract infections (UTIs) dominate in adulthood [18]. In a Korean cohort of 47 children with VACTERL (2011–2019), 89.4% had renal anomalies; with a mean follow-up of 3.26 years, half had UTIs (83.3% of these recurrent), 23 had VUR, 20 had acute kidney injury (20% of these progressed to chronic kidney disease, CKD, and 2 needed kidney replacement therapy), and the prevalence of CKD stages 2–5 of the KDIGO classification was 14.9%; complex renal anomalies and stage 3 acute kidney injury were associated with a risk of progression about 11 and 9 times higher [130]. At a San Diego centre, 8 of 12 patients with VACTERL and CKD 2–5 reached end-stage kidney disease, versus 4 of 12 controls with similar urological anomalies, with more complications of peritoneal dialysis, lower creatinine clearance 2 years after transplantation (65.8 versus 87.8 mL/min/1.73 m²) and shorter stature (−2.34 versus −1.27 standard deviations) [131]. Across congenital anomalies of the kidney and urinary tract (CAKUT), unilateral renal agenesis occurs in 0.15 and bilateral agenesis in 0.12 per 1,000 newborns (M:F ratio 2.45:1), and VATER/VACTERL is among the syndromes with renal agenesis, alongside MURCS, BOR and Fraser; extrarenal defects predict worse renal survival [132].

3.7. Limb component

Radial ray defects range from radial club hand with a single forearm bone and absent thumb to mild forms with minimal thumb abnormality; about 50% of affected children have other anomalies, with a strong association with haematological and cardiac disorders [64]. In the EUROCAT classification of limb reduction defects, reproduced by the Oxford Desk Reference, radial aplasia with absent thumb is a longitudinal defect, the VACTERL pattern, whereas radial aplasia with an intact thumb, typical of TAR, is intercalary [133]. The classic defect is preaxial: hypoplasia or aplasia of the thumb and radius, triphalangeal thumb, radioulnar synostosis, syndactyly and preaxial polydactyly; it is usually bilateral, but may be asymmetric, and a reduced thenar mass is the mildest form [2, 107, 134]. In VACTERL the thumb is often absent, unlike thrombocytopenia-absent radius (TAR) syndrome, and there is no thrombocytopenia [135]. Smith's records a lower limb defect in 23% [2], whereas the Oxford Desk Reference states that the lower limbs are not affected [107]; Castori and colleagues, reviewing 25 patients with VACTERL and lower limb malformations, found hypoplasia or aplasia of the tibia as the most common finding (68%) and fibular ray involvement in 20% [1]. Polydactyly and lower limb anomalies may, according to Solomon, have been attributed to VACTERL in error in some series [10]; in the EUROCAT series, only radial ray anomalies counted as a component, and the lower limbs were affected in 13% [17].

3.8. Other manifestations

Less frequent defects include prenatal and postnatal growth deficiency, ear anomalies, large fontanelles, rib anomalies and external genital defects; prenatal growth deficiency and single umbilical artery are non-random features [2]. Single umbilical artery may be the first prenatal clue [10]. The GeneReviews on McKusick-Kaufman syndrome states that hydrometrocolpos may be part of VACTERL and includes hexadactyly among the limb anomalies [136].

3.9. Neurocognitive development and growth

Most children have normal brain function, although early growth and progress may be slow because of the malformations and surgery [2, 65]. A neurocognitive deficit should strongly suggest an alternative diagnosis [10], and about 80% of the geneticists surveyed by Solomon consider that facial dysmorphism or an unexplained neurocognitive deficit changes the diagnostic impression [43]. In the 11 NIH adults, mean height was 170.2 cm in men and 159 cm in women [18]. In a French prospective cohort of 74 infants with OA, 13 (18%) had a global Ages and Stages Questionnaire (ASQ) score of 185 or less at 24 months, mainly in communication and socialisation; after adjustment for gestational age and genetic anomalies, prolonged hospital stay was associated with a worse result and greater weight-for-age with a better one [137]. In the Spanish OA cohort, neurodevelopment was adequate in 88.5% of those followed for more than 12 months [126].

3.10. VACTERL with hydrocephalus

Central nervous system defects are rare in classic VACTERL [51]. In VACTERL-H, hydrocephalus often results from aqueductal stenosis, and a poor prognosis is the rule, although there are survivors with a good outcome [2, 19]. The index patient of Sujansky and Leonard had hydrocephalus, TOF, a heart defect, renal hypoplasia and bilateral agenesis of the radii and thumbs and died at 4.5 months; the two siblings died in utero with similar malformations [3]. Iafolla and colleagues described three unrelated infants with aqueductal stenosis and VATER features: one died of respiratory failure and two survived (30 and 19 months) after early neurosurgery, and the authors advised against labelling the disorder as uniformly lethal [3]. Froster and colleagues described two siblings with VACTERL-H and branchial arch defects (ear malformation with external auditory canal atresia, cleft palate); Lomas and colleagues, four males of one family with symmetric radial anomalies, renal anomalies, anal atresia, hypoplastic penis, heart defect and aqueductal stenosis, with ultrasound diagnosis possible at 20 weeks [6]. In FANCB cases, the major signs are ventriculomegaly, bilateral absence of thumbs and radii, vertebral defects, renal agenesis and growth retardation [20]. In a boy with hydrocephalus, the Oxford Desk Reference recommends looking for congenital adducted thumbs and hypoplasia of the thumb and radius, the latter suggestive of X-linked VACTERL-H, whose known genes are FANCB and ZIC3 [138, 139]. The differential is X-linked hydrocephalus due to L1CAM (Xq28: aqueductal stenosis, adducted thumbs, spastic paraparesis, hypoplasia of the corpus callosum and intellectual disability), whose molecular detection rate is 75% in families with three affected males and 15% without a family history [138]. In the six boys with FA-B brought together by Holden (four from Meetei and two from his own family), intrauterine growth restriction and bilateral radial defects were present in 6/6, and cephalic and renal anomalies and hypogonadism in 5/6, and hydrocephalus had different mechanisms (patent aqueduct, Arnold-Chiari malformation or aqueductal stenosis) [52].

3.11. VACTERL phenotype in Fanconi anaemia

In FA, the combination of renal and radial anomalies is the signature of the VATER phenotype, present in 93%, and these patients have shorter median survival and earlier neoplasms [29]. According to FARF, the most frequent anomalies in retrospective analyses are short stature (43%), radial ray anomalies (40%), café-au-lait spots (37%), renal malformations (27%), microcephaly (27%) and male genital anomalies (16%); up to 40% of patients (range 10–40%) have no physical anomaly at all, so the absence of dysmorphic features does not exclude FA, the median age at diagnosis is 7 years and at least 10% are diagnosed at 16 years or older [11]. More than 16% of 370 patients had malformations without haematological abnormalities at diagnosis [43]. About 7% of patients with FA have digestive anomalies (OA in about 1.4% and TOF in about 3.5%, duodenal atresia and ARM), usually corrected before the diagnosis of FA [11]. In the Portuguese cohort, the median age at diagnosis was 6 years (0–35), and only 13% presented with morphological abnormalities alone, versus 47% with haematological and morphological abnormalities [68]. Smith's reports a mean life expectancy of 20 years (from birth to 50) and infertility in all men [9]. Bone marrow failure may therefore appear years after a diagnosis of VACTERL that did not exclude FA.

3.12. Natural history in adulthood

In the 11 adults of the NIH cohort (28 to 64 years, mean 40 years), about 25% of the clinically significant malformations had not been identified in childhood (40% of vertebral, 50% of cardiac and 50% of renal malformations) [18]. Six patients (55%; 60% of those with vertebral anomalies) reported back pain linked to the vertebral malformations, which began earlier than in the general population; five (45%; four of the six with TOF) had dysphagia and/or reflux; three (27%; half of the patients with TOF) had symptoms of reactive airway disease; five (45%) had UTIs and/or urolithiasis, but only one had reduced renal function [18]. Anorectal sequelae included severe constipation and obstructions requiring hospital admission, and most adults were not being followed up for VACTERL [18]. In adults with OA, dysphagia (85% versus 2% in 287 controls, in the Finnish study by Sistonen of 101 adults with a native oesophagus followed for a mean of 36 years) and symptomatic GORD (34% versus 8%) persist, and adults underestimate their symptoms because they are used to them [127, 140]. In the INoEA systematic review, the pooled prevalence of Barrett's oesophagus was 5.0% (95% CI 4.5–5.6%; 317/6,282 patients), with a mean age at detection of 13.8 years, versus 0.5–2% in adults in the general population, and 14 oesophageal cancers were described in adults with OA (4 adenocarcinomas and 10 squamous cell carcinomas; median age 44 years), only 3 with documented Barrett's [140]. In the Rotterdam cohort of 271 adults with OA under endoscopic surveillance, Barrett's was present in 19 (7%; median age 32.3 years), appeared in a further 4 during follow-up (0.8% per year), without dysplasia or cancer in those under surveillance, and the two squamous cell carcinomas diagnosed during the study occurred in patients who were not under surveillance [141]. In adults with ARM, eUROGEN acknowledges a possibly increased risk of colorectal cancer in young adults, with no established risk or evidence justifying specific screening [142]. The sequelae by component are summarised in the following table.

Source: [10].

3.13. Cancer risk

The GOBACK study, which linked birth defect, cancer and birth registries from eight US states (21,224,742 births between 1990 and 2018), identified 2,288 children with VACTERL, excluding VACTERL-H, chromosomal anomalies and known syndromes, without systematic genetic testing [110]. With a median follow-up of 7.9 years, there were 8 cancers, 5 (62.5%) embryonal and none haematopoietic; the incidence was 421.3 per million person-years (95% CI 181.9–830.0), versus 133.4 in children without defects, with an adjusted hazard ratio (HR) of 3.0 (1.5–6.0) for any cancer and 6.9 (2.9–16.5) for embryonal tumours [110]. The risk did not differ significantly from that of children with three or more non-VACTERL defects (HR 3.1); with a broader definition (n=2,843), there were 16 cancers and an HR of 7.9 [110]. The absence of haematological cancers makes undiagnosed FA unlikely as the sole explanation, but the study did not exclude predisposition syndromes, has low power and does not propose a screening protocol [110]. The 8 cases observed do not allow a lifetime risk to be estimated.

4. Clinical Recognition and Warning Signs

4.1. When to suspect

Suspicion almost always arises from one component. Any newborn with OA/TOF or ARM should be assessed for the other components, because these patients frequently have additional anomalies, and the same approach applies to any child with two components [19, 115]. The eUROGEN guideline for ARM expressly asks for the anomalies of the VACTERL association to be sought in the neonatal diagnostic phase [115]. When one component is identified, the others should be sought, and a malformation that is unusual in VACTERL justifies further investigation [2]. Diagnosis at later ages is not rare, and the neonatal diagnostic approach also applies at those ages [19]; in the NIH adults, about a quarter of the significant malformations were only identified after childhood [18]. In ARM, the presence of at least two VACTERL components was associated with heart disease in a cohort of 314 patients (OR 4.8) [123]. In the history of digestive atresias, the Oxford Desk Reference includes a three-generation family history (with neonatal surgery and colostomies), consanguinity, maternal diabetes, teratogens, polyhydramnios and twinning or early loss of a co-twin, and on examination looks for hypoplasia of the radius or thumb, digital anomalies (Feingold), ear tags and ear shape anomalies (Goldenhar, CHARGE, Townes-Brocks), corneal clouding (Fryns) and colobomas (CHARGE); the anus and genitalia should be described and photographed before surgery [63, 65]. In infants of diabetic mothers, it recommends radiography of the lumbar spine and sacrum [63].

4.2. Signs suggesting an alternative diagnosis

VACTERL is a diagnosis of exclusion, and some findings change the hypothesis [38, 143]. In Fanconi anaemia, pigmentary changes (café-au-lait spots), growth retardation, microcephaly, microphthalmia, bilateral thumb and radius anomalies and consanguinity carry weight [67, 107]. The combination of renal and radial anomalies occurs in 93% of patients with the VATER phenotype and FA [29]. Facial dysmorphism, unexplained neurocognitive deficit, craniosynostosis (Baller-Gerold), coloboma (CHARGE), hydrocephalus (VACTERL-H), macrocephaly (PTEN), hypocalcaemia (22q11.2 deletion), heterotaxy (ZIC3), refractory hypoxaemia with pulmonary hypertension (ACDMPV due to FOXF1), autosomal dominant inheritance of components (Townes-Brocks) and cytopenia (FA, Diamond-Blackfan anaemia, TAR) are the main red flags [10, 43, 96]. Anorectal malformation with a triphalangeal thumb and dysplastic ears suggests Townes-Brocks, and postaxial polydactyly with imperforate anus suggests Pallister-Hall, in which a bifid epiglottis, rare in other syndromes, helps the diagnosis [10, 144, 145]. Adducted thumbs with spasticity in a boy with hydrocephalus point to L1CAM [138]. Abnormal segmentation of 10 or more contiguous vertebrae defines spondylocostal dysostosis and rules out the segmental defects of VACTERL [146]. FARF recommends testing for FA in all children with multiple anomalies, especially those of the PHENOS acronym and those of VACTERL-H, and in any child with an isolated thumb anomaly or radial deficiency [11].

4.3. Emergency situations

OA requires cessation of oral feeding, continuous aspiration of the oesophageal pouch with a Replogle tube, an elevated position and intravenous fluids; non-invasive ventilation should be avoided, and, if ventilation is needed, intubation is preferred, because of the risk of gastric distension through the fistula [12, 147]. ARM should be diagnosed in the first 24–48 hours, with digestive decompression and intravenous nutrition [19, 115]. Critical heart defects, bilateral renal agenesis and hydrocephalus with raised intracranial pressure are emergencies in their own right, and severe heart defects and imperforate anus are among the malformations requiring neonatal surgery [10]. Right aortic arch should be excluded by echocardiography before OA repair, because it changes the surgical approach [147]. Any OA without air in the abdomen should be presumed to be long-gap (2021 ERNICA consensus, 100%) [148]. ARM does not, as a rule, require emergency surgery at birth, even in high forms, which allows time for coordination with the reference centre, but potentially lethal disease, especially congenital heart disease, should be excluded in the first 24 hours [149, 150]. The adrenal insufficiency of Pallister-Hall syndrome requires urgent treatment [145].

4.4. Newborn screening

There is no population newborn screening for VACTERL. Targeted assessment should run in parallel with routine newborn hearing and blood spot screening, because hearing loss, for example, points to Townes-Brocks syndrome [19].

5. Diagnosis: Criteria, Tests and Algorithms

5.1. Clinical criteria

There is no consensus on strict criteria and no laboratory test that confirms VACTERL [10, 49]. The formulations in use are shown in the following table.

The Oxford Desk Reference attributes the domain criterion to «Hall et al. (1989)» on p. 58, but the corresponding reference in the section list is the Handbook of normal physical measurements by Hall JG, Froster-Iskenius and Allanson, a work on anthropometric measurements; on p. 297 it attributes it to «Hall (2001)» and lists as its source the chapter by Hall BD on the VATER/VACTERL association in Management of Genetic Syndromes (3rd edition, 2010, pp. 871–878), updated by Solomon and Hall in the 4th edition (2021, chapter 61) [65, 107, 151, 152]. The source of the criterion is therefore Hall BD's chapter; its text was not consulted, and the formulation reproduced is that of the Oxford Desk Reference. In the survey of 121 clinical geneticists (61% from the USA), 79% required at least three components, 7% at least four and 15% only two; the vertebral, anal and TOF components were considered defining by at least 90%, the renal by 85%, the cardiac by 82% and the limb components by 71% [43]. For counting purposes, isolated PDA and PFO are not a cardiac component [10].

5.2. Assessment of the components

The Brazilian textbook summarises the examinations by component: echocardiography for heart defects; radiography, CT, ultrasound and MRI of the spine for skeletal defects; contrast radiography for TOF and ARM; and renal ultrasound, CT or MRI for renal anomalies [143]. In OA, postnatal detection rests on inability to pass a nasogastric tube, with the tube coiled in the pouch on radiography, tracheal deviation and absence of the gastric bubble (which suggests OA without TOF or with proximal TOF); three-dimensional chest CT is possible and barium is rarely needed [12]. When ZIC3 is suspected, assessment includes echocardiography and cross-sectional imaging of atrial situs, abdominal ultrasound or CT of visceral situs and the spleen, a search for Howell-Jolly bodies on the blood film, an upper gastrointestinal contrast study for rotation anomalies, renal ultrasound and radiographs of the spine and limbs [30]. The component guidelines do not agree on preoperative imaging in OA: the ERNICA consensus conference approved routine echocardiography (100% of votes), mainly to exclude a right-sided descending aorta, but did not approve abdominal and renal ultrasound (40%) or spinal ultrasound (6.7%) as routine preoperative tests, and placed abdominal and renal ultrasound on a checklist before first discharge [147]. In the 2021 ERNICA consensus on long-gap OA, routine abdominal ultrasound including the kidneys and urinary tract in the first week of life obtained 100% agreement (20/20), indicating that the divergence concerns timing (preoperative or first week) and not the need for the examination [148]. The Solomon 2014 approach and the eUROGEN guideline for ARM recommend renal and spinal ultrasound in the neonatal period [19, 115]. In the Amsterdam OA cohort, complete VACTERL screening went from partial to 100% between 2020 and 2024, and found VACTERL in 28% of those screened [117].

5.3. Exclusion of Fanconi anaemia

A chromosome breakage study in lymphocytes with DEB is indicated in all patients with VACTERL [19], and Smith's recommends that it be «seriously considered in all cases» [2]. Faivre and colleagues advocated testing not only in VACTERL-H, but also in VACTERL with radial anomalies, especially with abnormal pigmentation, growth retardation, microcephaly or microphthalmia [67]. The diagnosis of FA rests on increased breakage and radial figures with DEB and MMC and/or on identification of biallelic variants in one of the autosomal recessive genes, a heterozygous variant in RAD51 or a hemizygous variant in FANCB [14]. If somatic mosaicism is suspected, testing in skin fibroblasts is indicated, because haematopoietic reversion may make the blood result normal [8, 14]. FANCB carriers are not detected by the breakage test, and carrier testing is only possible after the familial variant has been identified [8, 14]. The test is efficient and accessible, and the result changes counselling (recessive or X-linked) and haematological and oncological surveillance [10]. Background breakage in controls is more variable with MMC, so some centres use DEB only and others DEB and MMC; breakage confirms FA but does not identify the gene, and fragility with DEB or MMC may occur in some patients with Seckel or Nijmegen syndrome, who should be tested molecularly [14].

FARF considers the DEB breakage test the gold standard (MMC has more false positives) and proposes an algorithm: breakage in lymphocytes; if positive, an FA gene panel with deletion and duplication analysis; if the panel is negative, exome, genome or research testing [11]. Genetic testing is increasingly used as the first line in newborns and children with multiple congenital anomalies, but FARF recommends both tests in all suspected cases, and, if breakage testing is not available, the diagnosis can be confirmed by genetic testing [11]. The analysis should include 50 metaphases per culture (25 if more than 30% have radial figures), and the test is considered positive when the percentage of cells with radial figures in the DEB culture is 30% or more; a negative or equivocal result with strong clinical suspicion requires study of skin fibroblasts, because 15–20% of patients have some degree of mosaicism (abnormal fibroblasts and normal lymphocytes) and reversion in haematopoietic stem cells is documented in less than 5% [11]. A negative molecular test with positive breakage may result from a gene not included, an undetectable variant, an unknown gene or mosaicism [11]. In the Portuguese cohort, the DEB test (0.5 μg/mL) proved accurate, with no complex radial figures in any control, and there were two somatic reversions years after diagnosis, which justifies repeating the test in the event of an unexpected course [68]. In practice, uptake is low: about two thirds of the geneticists surveyed never tested for FA or tested for it in fewer than 25% of cases [43]. In the NIH cohorts, more than 100 patients with VACTERL tested with DEB did not have FA (one with a myelodysplastic phenotype was being studied for skin mosaicism) [43], and Tark found no haematological cancers among children with VACTERL [110]. The probability of FA in VACTERL without additional signs is therefore low, but the recommendation to test everyone stands in the sources consulted. The indications differ in detail: Solomon (2012, 2014) and the GeneReviews on FA propose testing all patients with VACTERL, FARF requires it in multiple anomalies of the VACTERL-H or PHENOS type and in any isolated radial or thumb deficiency, Faivre (2005) restricted it to VACTERL with radial anomalies or signs of FA, and Bowden (2026) includes it in the baseline panel [11, 14, 19, 21, 43, 67].

5.4. Genomic tests: order and yield

The yield is lower when strict VACTERL criteria are applied and higher in cohorts with complex phenotypes, defects outside the acronym or neurocognitive deficit [55, 153]. In trio-exome studies, most diagnoses were de novo [55]. The Solomon 2012 algorithm proposed, for classic VACTERL without evidence of an overlapping condition, two tests for everyone: microarray and FA testing [43]. The Solomon 2014 approach added exome or genome sequencing and panels, and retained high-density microarray, with high-resolution karyotyping when it is not available [19]. The systematic review by Bowden and Martinez (2026), without meta-analysis and with provisional recommendations, proposes imaging, full blood count with film, microarray, chromosome breakage study and exome or genome in all patients with at least two components and in selected cases with a single isolated component [21]. The Philadelphia group recommends replacing microarray with exome or genome with CNV analysis [22]. In the presence of features of trisomy 18 or triploidy, QF-PCR or FISH gives a rapid result [107]. The Genomics England PanelApp panel «VACTERL-like phenotypes» (version 1.35, November 2025) has 62 genes, 19 of them green: CDX2, CHD4, CHD7, EFTUD2, FANCB, FGF10, HAAO, HOXA13, KYNU, MYCN, PLVAP, PUF60, SALL1, SALL4, TBX3, TBX5, TRAP1, WBP11 and ZIC3 [78]. FOXF1, FANCA, RAD51 and RPL18 are not part of that panel, and the RPL18 family shows that a restricted panel can miss a ribosomopathy [78, 96]. GeneReviews mentions a VACTERL multigene panel that may include HAAO, KYNU and NADSYN1, and proposes exome or genome sequencing when the phenotype is indistinguishable from other multiple congenital malformation syndromes [40]. The retired OA/TOF chapter recommended, in the aetiological work-up, a three-generation family history, a karyotype if aneuploidy is suspected, a multigene panel with deletion and duplication analysis, a microarray if there are features of a contiguous gene syndrome and exome or genome sequencing, with exome array if the exome is not diagnostic [12]. In the EUROCAT database, only 16 of 29 registries performed genetic testing to exclude alternatives, mainly karyotype and microarray [17].

5.5. Limits of tests

The exome does not detect repeat expansions or deep intronic variants [55]; the ZIC3 polyalanine expansion is an example of a variant that requires attention to repeat regions [53], and HOXD13 polyalanine expansions may escape exome and panel testing and require targeted sizing [59]. ACDMPV may result from deletions of the enhancer upstream of FOXF1, so a normal coding sequence does not exclude the diagnosis [31]. About 30% of FANCB variants are deletions or duplications requiring CNV analysis [8]. Mitochondrial DNA heteroplasmy varies between tissues, and a negative result in lymphocytes does not exclude the variant in another tissue [1]. Somatic reversion in FA may normalise the breakage test in blood [14]. Rare CNVs inherited from healthy parents are mostly of uncertain significance or modifiers [60, 103]. A non-diagnostic exome or genome does not exclude a genetic cause and justifies storing DNA and reanalysing the data [12, 43]. Panel sensitivity varies between laboratories [12]. None of the sources consulted provides a clinical sensitivity for VACTERL as a whole, because there is no reference standard; the yields in the previous table are proportions of diagnoses and not sensitivities.

5.6. Genetic report, variants of uncertain significance and segregation

The report should state the gene, the reference transcript with its version (MANE Select), the variant in HGVS nomenclature (c. and p.), the genomic coordinate, the zygosity, the origin when the study is a trio, the class according to the criteria of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology (ACMG/AMP) and the gene-phenotype relationship [37, 70]. The experience with TRAP1 and ZIC3 shows that variants published as causal may become benign, and that with HOXD13 that they may become of uncertain significance: the current ClinVar classification should be checked before using a variant from the literature [37]. A VUS in FA or CNDD genes neither establishes nor excludes the diagnosis [14, 40]. A variant of uncertain significance (VUS) should not guide prenatal diagnosis or counselling without family segregation and, if possible, functional studies, as in the RPL18 family, in which the variant was present in all affected members and the mutant protein degraded faster [96]. Secondary findings, such as the m.3243A>G variant in the Ćomić cohort, should be reported with the uncertainty about causality [55].

5.7. Methylation episignature

The RCEM episignature was developed in 53 patients (positive in 40) and validated in a preprint in 18 of 21 patients with VACTERL [58, 111]. The authors of the validation state that it is available on the EpiSign V5 platform; this availability was not confirmed in a laboratory source [111]. A positive result supports classification in the RCEM category, but does not identify the cause, does not exclude a monogenic phenocopy and does not replace FA testing or exome or genome sequencing.

5.8. Prenatal diagnosis

ARM and OA/TOF often go unnoticed before birth; vertebral, cardiac, renal and limb anomalies are more detectable [10]. Less than half of ARMs are diagnosed prenatally [115]. In OA, the most reliable sign is the distended oesophageal pouch, and accuracy increases when an anechoic area is identified in the middle of the fetal neck; the predictive value of an absent stomach with polyhydramnios is probably even lower in fetuses with multiple anomalies [12]; in a series of 87 fetuses with a small (n=53) or absent (n=34) stomach, the positive predictive value of the combination of absent stomach with polyhydramnios was 56% and the sensitivity of ultrasound for OA 42%, and only 1 in 12 fetuses with polyhydramnios has OA [12]. About one third of digestive atresias are detected prenatally, 40% of these before 24 weeks [74]. In ARM, a dilated distal colon without an anal «target sign» suggests a high form, visualisation of the target sign may help to detect low forms, and a cystic pelvic mass consistent with hydrocolpos should raise suspicion of cloaca even if it disappears, with fetal MRI to be considered [115]. eUROGEN recommends a detailed ultrasound between 18 and 22 weeks when the risk of anomalies is increased [115]. The radius and ulna are identifiable from the start of the second trimester, but thumb hypoplasia is only detected when bones are absent [107]. Single umbilical artery should prompt a targeted anomaly scan [10]. Polyhydramnios (deepest vertical pocket above 8 cm) occurs in 1–2% of pregnancies, about 8% of these have additional fetal anomalies on ultrasound and up to 60% are idiopathic; the assessment looks for a small or absent stomach (OA/TOF), the double bubble sign, renal agenesis and heart defects, and fetal microarray and targeted tests, ideally as a trio, have a growing role [154]. In maternal diabetes, the ultrasound detection rate of fetal anomalies was 30% in diabetic women versus 73% in non-diabetic women, and a periconceptional HbA1c above 9% was associated with 14.3% major anomalies (Wong 2002) [104]. When TAR is suspected because of radial ray defects, prenatal testing by chorionic villus sampling or amniocentesis is possible, and in Holt-Oram syndrome ultrasound can identify severe skeletal and cardiac defects [107]; prenatal diagnosis of FA requires prior contact with the laboratory [64]. When suspicion arises, high-resolution ultrasound, fetal MRI, chromosomal and molecular studies and a genetics consultation are recommended [12]. In 16q24.1 deletions, prenatal findings are non-specific (increased nuchal translucency, cystic hygroma in the first trimester and cardiac, renal and intestinal malformations from 20 weeks), and diagnosis by ultrasound alone is not reliable [31]. Holden recommends fetal ultrasound targeted at the radial ray, cerebral ventricles and kidneys in women at risk of FA-B, noting that prenatal diagnosis requires breakage and molecular studies, and that skewed X inactivation in the mother of a boy with VACTERL-H should raise suspicion of FA-B [52]. The ERNICA consensus recommends that prenatal suspicion of OA lead to multidisciplinary prenatal counselling in a specialist centre (100%), and the long-gap consensus the same referral (95.7%) [148, 155]. Chromosome breakage studies are possible on fetal material, as in the Holden family, in which the chromosomes of the affected fetus showed increased sensitivity to DEB [52]. Targeted prenatal or preimplantation diagnosis is only possible when the familial variant is known [12, 14].

5.9. Practical algorithm

The algorithm results from combining Solomon 2012 and 2014, Bowden 2026 and the component guidelines [19, 21, 43, 115, 147]:

6. Differential Diagnosis

6.1. Comparative table

6.2. Fanconi anaemia

FA is the first differential to exclude because it may share all the components, has haematological and oncological consequences that can be managed with surveillance and transplantation, and changes the recurrence risk to 25% (autosomal recessive) or to 50% of the male children of a female carrier (FANCB) [10, 14]. Renal and radial anomalies together (93% in the VATER phenotype with FA), pigmentation, microcephaly, microphthalmia, growth retardation and consanguinity increase the probability, but the absence of these signs does not exclude FA, and up to 40% of patients with FA (range 10–40%) have no physical anomalies [11, 29, 67]. The café-au-lait spots of FA appear over time, so pigmentation should be reassessed during follow-up [64]. FARF considers that the breakage test resolves the dilemma between VACTERL and FA in children with radial and renal anomalies [11]. In the radial ray, FA gives absent, hypoplastic, supernumerary or bifid thumbs and hypoplastic or absent radii, with other skeletal problems (vertebral, rib) in 20% [64]. Rossbach and colleagues described siblings with FA initially diagnosed as VACTERL-H and later as Baller-Gerold, illustrating the need for breakage testing in Baller-Gerold as well [159].

6.3. Monogenic causes with hydrocephalus, heterotaxy or macrocephaly

Hydrocephalus in a patient with VACTERL components requires study of FANCB, the other FA genes and ZIC3 [19, 138]. Heterotaxy, asplenia or an abnormal situs point to ZIC3 and to the heterotaxy and isomerism spectrum [6, 54]. Macrocephaly with ventriculomegaly points to PTEN, with the caveat that the relationship with VACTERL rests on a single patient [3, 36].

6.4. Alveolar capillary dysplasia with misalignment of the pulmonary veins

A newborn with VACTERL components and hypoxaemia or pulmonary hypertension disproportionate to the heart defect should have FOXF1 and the 16q24.1 region studied, because ACDMPV is usually lethal and the prognosis changes the discussion of treatment with the family, including that of lung transplantation [31, 43]. In the series published between 2018 and 2025, mean survival without transplantation was about 7 months [31].

6.5. Congenital NAD deficiency disorder

CNDD results from biallelic variants in HAAO, KYNU or NADSYN1, which block de novo synthesis of NAD from tryptophan through the kynurenine pathway, and mimics VACTERL [40]. Up to 2023, 27 individuals from 25 families had been described (16 alive, the oldest aged 30 years): heart defect in 25/25 (hypoplastic left heart in 8 and tetralogy of Fallot in 3), short stature in 12/13 (92%), vertebral anomalies in 18/26 (69%), developmental delay or intellectual disability in 8/13 (62%), renal anomalies in 16/27 (59%), dysmorphic features in 12/26 (46%), shortened limbs in 10/27 (37%), limb anomalies in 7/24 (29%), microcephaly in 7/24 (29%), neuromuscular abnormalities in 6/27 (22%), deafness in 4/27 (15%) and syndactyly in 4/26 (15%) [40]. There were nine deaths: five terminations or fetal losses and four in the first year [40]. Anal anomalies and TOF are rare, and disproportionate short stature, developmental delay and dysmorphism are more common than in VACTERL [40]. There are no consensus clinical criteria; suggestive findings include left-sided, right-sided or both-sided heart disease, renal anomalies (aplasia, hypoplasia, dysplasia), butterfly, hemi-, wedge or fused vertebrae, shortened long bones in all four limbs, short metacarpals with accessory ossicles, hyperphalangism, cutaneous syndactyly, short stature (z from +0.25 to −6.1), microcephaly (z from −2.3 to −6.4), sensorineural deafness, sacral dimple, clubfeet and a family consistent with autosomal recessive inheritance; there is no recognisable facial gestalt and no genotype-phenotype correlation, and four patients had normal development [40]. Bone marrow failure and cancer predisposition, characteristic of FA, have not been described in CNDD [40]. Sequencing detects more than 99% of variants; deletions are rare (one homozygous deletion of exon 5 of KYNU through maternal uniparental isodisomy), and biallelic KYNU variants also cause hydroxykynureninuria, with urinary excretion of xanthurenic acid and 3-hydroxykynurenine, metabolites described in CNDD only in research [40]. In the mouse, maternal niacin supplementation prevented malformations in Haao- and Kynu-null embryos [82]; in the Nadsyn1 model, any vitamin B3 vitamer prevented embryonic loss and malformations in heterozygous mothers, but null mothers needed amidated precursors (nicotinamide or nicotinamide mononucleotide) [83]. There is no human trial, dosing regimen or human pregnancy outcome, and GeneReviews does not recommend niacin [40, 169, 170]. Saudubray's textbook, which predates these series, described NADSYN1 deficiency in 5 individuals from 4 families [84].

6.6. Townes-Brocks, Feingold, Holt-Oram and other autosomal dominant syndromes

Autosomal dominant transmission of components suggests Townes-Brocks [10]. In Townes-Brocks syndrome due to SALL1 (16q12.1; mainly truncating variants in exon 2 or intron 2, detected by sequencing in more than 90% of cases), severe vertebral anomalies and TOF have not been observed, and VACTERL is the main differential in sporadic cases [144, 171]. GeneReviews estimates the recurrence risk for siblings and offspring in VACTERL at about 1%, considers it the main differential in simplex cases of suspected Townes-Brocks, and notes that radial aplasia and thumb aplasia have not been observed in SALL1-related disease, so radial involvement or a Duane anomaly points first to SALL4 [144]. Feingold syndrome is distinguished by microcephaly, brachymesophalangy and syndactyly of the toes [157]. In Holt-Oram syndrome, only the upper limbs are affected, with 100% penetrance, with skeletal defects that are always bilateral and usually asymmetric, from clinodactyly to severe reduction of the arm (4.5%), and the Oxford Desk Reference states that TBX5 sequencing detects about 25% of sporadic and 53% of familial cases [107]. Nager syndrome results from haploinsufficiency of SF3B4 and Okihiro syndrome from SALL4 variants; Roberts syndrome shows premature centromere separation on routine karyotyping [64, 107]. In the van de Putte series, Townes-Brocks, Duane-radial ray and Opitz G/BBB syndromes always included ARM or OA/TOF with at least two other components, and a SALL4 variant inherited from a mother with a short thumb changed the recurrence risk to 50% [57].

6.7. Overlapping associations and spectra

MURCS, OAVS, OEIS, LBWC and pentalogy of Cantrell overlap with VACTERL and have been grouped with it in RCEM; when MURCS overlaps, it is usually considered VACTERL with uterovaginal anomalies [50, 62]. Twenty-four cases of co-occurrence of two RCEM have been described [50]. A group of patients with rhombencephalosynapsis and VACTERL features is related to Gómez-López-Hernández syndrome, in which all cases were sporadic and at least two had holoprosencephaly [172]. In the differential of MURCS, the VATER association is distinguished by oesophageal stenosis or TOF [161], and in that of Edwards syndrome by a normal karyotype [165]; VACTERL also appears in the differential of Goldenhar syndrome [162]. In the differential table of the GeneReviews on Baller-Gerold, VACTERL appears as sporadic, of unknown cause, with hypoplasia or aplasia of the thumb, whereas Baller-Gerold has bilateral, symmetric radial defects, craniosynostosis and sometimes poikiloderma [159, 160].

6.8. Differential diagnosis of oesophageal atresia itself

Laryngotracheo-oesophageal cleft may be associated with TOF and gives polyhydramnios and a small stomach prenatally and aspiration after birth; oesophageal webs and rings, congenital oesophageal stenosis, diverticulum, tubular duplications and congenital short oesophagus present later or with vomiting and dysphagia; tracheal agenesis or atresia gives hyperechogenic lungs and flattened diaphragms in the fetus and, at birth, severe respiratory distress, absent cry and failure of ventilation despite intubation [12]. OA/TOF has also been described in Opitz G/BBB and Pallister-Hall syndromes, without being a major feature [12]. Duodenal atresia is due to trisomy 21 in 30–50% of cases [74]. Caudal regression, sporadic or linked to maternal diabetes, forms a spectrum with imperforate anus, sacral agenesis and sirenomelia [65, 105].

7. Treatments and Risk Management Strategies

7.1. Principles

There is no treatment for the association as an entity; treatment is that of each component, decided by a multidisciplinary team and, ideally, in an experienced centre [10, 155]. It takes place in two phases: neonatal surgical correction of malformations incompatible with life (severe heart defects, imperforate anus, OA/TOF) and long-term management of sequelae [10]. The order of interventions depends on the severity of each component, and prior vascular and cardiac assessment determines the anaesthetic plan and the surgical approach [19]. Early developmental interventions are indicated; in the USA, children are eligible for services under the Individuals with Disabilities Education Act (IDEA), and Solomon and colleagues suggest, when available, follow-up by a paediatric physiatrist every 3–6 months [19]. When FA is identified, haematological and oncological management, including haematopoietic stem cell transplantation, follows the Fanconi anaemia recommendations [14].

7.2. Oesophageal atresia and tracheo-oesophageal fistula

In the preoperative period, a Replogle tube in the upper oesophageal pouch, with continuous low-pressure suction, spontaneous breathing and, if ventilation is needed, intubation instead of non-invasive ventilation achieved 100% ERNICA consensus [147]. Antibiotic prophylaxis from diagnosis and placement of a central venous or arterial catheter before transfer to theatre did not achieve consensus [147]. Surgery consists of closure of the TOF and oesophageal anastomosis; it is postponed in low birth weight, pneumonia or other major anomalies, with parenteral nutrition, gastrostomy and pouch suction [12]. Delivery should take place in a hospital with neonatal intensive care and paediatric surgery [173].

The consensus conference of ERNICA (the European Reference Network for rare inherited and congenital digestive disorders) on the diagnosis and surgical treatment of OA/TOF generated the items at a meeting in Stockholm (2018), prioritised them by online survey and voted on 52 on a scale of 1 to 9, with consensus defined as at least 75% of voters between 6 and 9; the number of voters ranged from 13 to 18 per item [147]. The table reproduces all the items voted on.

Source: [147].

The 52 items were supported by 116 articles, of which only 5 (4.3%) were level 1 randomised trials (four trials and one pilot), 10 level 2, 26 level 3, 43 level 4 and 11 level 5; 20 items (38%) had full agreement, 37 (71%) consensus, and 13 received votes from 1 to 9 [147]. The panel was almost exclusively surgical (one paediatric gastroenterologist, no pulmonologist, anaesthetist or neonatologist), the conclusions rest mainly on expert opinion and apply to patients with primary anastomosis [147]. Routine preoperative MRI, preoperative measurement of the gap between pouches, routine posterior tracheopexy, glycopyrronium for leaks and the content of the discharge checklist were not voted on for lack of data [147]. For VACTERL, reading the tables shows that preoperative echocardiography achieved 100%, but renal and abdominal ultrasound (40%) and spinal ultrasound (6.7%) were not required before surgery; abdominal and renal ultrasound was included in the checklist before first discharge (100%) [147].

The 2021 ERNICA consensus on long-gap OA (97 items, 56 with full agreement and 90 with consensus) defined long gap as a gap of at least three vertebral bodies (76.2%), established that any OA without air in the abdomen is presumed to be long-gap (100%), preferred delayed primary anastomosis, at about 2–3 months of age according to gap assessment (100%), recommended avoiding cervical oesophagostomy and promoting sham feeding, and called for referral to centres experienced in oesophageal reconstructive surgery, preferably with more than two cases per year (91.3%); about 1 in 10 patients with OA does not allow primary anastomosis [148]. The FARF guidelines use another definition of long gap (more than 3 cm or more than two vertebral bodies; ultra-long from five vertebrae) [11].

The trials on which some items are based are small. In the Iranian double-blind trial by Askarpour (40 newborns), muscle-sparing thoracotomy left a smaller scar and earlier recovery of shoulder function, with no difference in intensive care stay, ventilation, Moro reflex or mortality [174]. Preservation of the azygos vein reduced postoperative pneumonitis (12% versus 56%) in an Indian study of 50 cases [175] and leaks (3/46, 6%, versus 10/50, 20%) in another of 96 newborns [176], but did not achieve consensus (71.4%), because the quality of the trials was questioned [147]. In the Great Ormond Street pilot trial (20 newborns with diaphragmatic hernia or OA/TOF), thoracoscopy was associated with intraoperative hypercapnia and acidosis (PaCO2 difference of 22 mmHg; 95% CI 2–42), an effect concentrated in diaphragmatic hernia and with no significant difference in OA/TOF [177]. In the Indian trial by Vaghela (42 newborns with leaks), glycopyrronium was associated with lower drain output (124 versus 370 mL) and more closures of the leak (16/21, 76%, versus 6/21, 29%) [178].

The most frequent complications are anastomotic leak, recurrent fistula, stricture and GORD [12]. The joint guideline of the European Society for Paediatric Gastroenterology, Hepatology and Nutrition and the North American Society for Pediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN-NASPGHAN, 2016), developed by the gastrointestinal working group of the International Network on Esophageal Atresia (INoEA), graded the literature using the Oxford Centre for Evidence-Based Medicine (CEBM) and GRADE, but, in the absence of therapeutic studies, all 36 of its statements are expert opinion, voted on by six experts using the nominal group technique [127]. The guideline recommends treating GORD with acid suppression in all patients with OA in the neonatal period, using proton pump inhibitors (PPIs) as first line and continuing treatment until the first year of life or longer, depending on the persistence of reflux disease, regularly reassessing the benefit and risk of prolonged use [127]. All patients, including asymptomatic ones, should undergo GORD monitoring (pH-impedance and/or endoscopy) when acid suppression is stopped and during follow-up [127]. Stricture dilatation is performed under general anaesthesia with tracheal intubation and over a guidewire, and routine screening and dilatation have not been shown to be superior to treating symptomatic strictures; three or more recurrences define a recurrent stricture, for which intralesional or systemic corticosteroids, topical mitomycin C, stents and an endoscopic knife may be considered [127]. Eosinophilic oesophagitis should be excluded, with biopsies proximal and distal to the anastomosis, in patients with dysphagia, reflux symptoms, cough, choking or PPI-refractory strictures before antireflux surgery [127]. Fundoplication may benefit patients with recurrent strictures, especially in long-gap OA, but severe oesophageal dysmotility predisposes to complications [127]. In cyanotic spells, assessment is multidisciplinary and should exclude strictures, recurrent or undiagnosed fistulas, congenital oesophageal stenosis, vascular rings, laryngeal clefts and aspiration; vascular malformations are excluded by CT or MR angiography [127].

Source: [127]. The guideline does not give PPI doses. In the data on adjuncts, intralesional triamcinolone gave inconsistent improvement, with potential complications (perforation, intramural infection, candidiasis, mediastinitis, adrenal suppression); topical mitomycin C (0.1 mg/mL) gave results similar to those of dilatation alone in a retrospective study of 21 patients; and fully covered metal stents were effective in 6 of 23 patients, versus 21 of 26 with custom-made dynamic stents, with a fistula between the oesophagus and an aberrant right subclavian artery as a major complication [127]. Dysphagia after fundoplication was 17.2% in OA versus 6.5% in other children in a series of 148 [127].

The ERNICA follow-up and organisation consensus voted on 29 items (25 on follow-up and 4 on organisation); 17 of the 25 had a corresponding ESPGHAN-NASPGHAN statement, with agreement on 14 of 17 (82.4%) and divergence on the duration of antacid therapy, mitomycin C and corticosteroids [155]. The text states consensus on 18 follow-up items (72%) and the table of the same manuscript on 19 (76%) [155].

Source: [155]. The four organisation items had 100% (18/18): multidisciplinary prenatal counselling in a specialist centre when OA is suspected; a minimum mean caseload of 5 new OAs per year for a specialist centre; treatment and follow-up, including transition, in centres with a multidisciplinary team; and parental participation in parent and patient associations as early as possible [155]. In the studies cited by ERNICA, 12 months of antacid prophylaxis did not reduce first-year strictures compared with 3 months (63 patients), and in another series of 128 patients prophylaxis did not reduce strictures; the results of mitomycin C are contradictory, and intralesional corticosteroids were being studied in the STEPS-EA trial [155].

7.3. Anorectal malformation

The ERN eUROGEN guideline (2025), adapted from the Dutch quality standard using the ADAPTE method, covers diagnosis (Part I), treatment (Part II), lifelong follow-up (Part III) and organisation of care (Part IV) [115, 142, 149, 150]. Most recommendations are grade D (expert opinion), and a genetics consultation in ARM with at least one other anomaly is one of the few with grade B [115].

Neonatal colostomy is usual in forms without a perineal fistula, with later reconstruction (pull-through) according to the anatomy and the continence prognosis [10, 156]. The American Pediatric Surgical Association guideline (APSA, 2024), based on 90 studies, does not recommend an optimal technique by subtype, considers loop or divided colostomy acceptable (the former with more prolapse) and found no difference between early and late repair [179]. The APSA functional outcomes guideline (109 studies, levels C–D) describes better continence rates in perineal and rectovestibular fistulas, improvement of symptoms with age, frequent urological anomalies and sexual and psychosocial problems, and calls for a structured transition [180]. The eUROGEN guideline was developed by a 15-member panel from 7 European countries, including 2 patient representatives (AIMAR and SoMA e.V.), with AGREE II assessment and grades A–D (A, consistent level 1 studies; D, expert opinion or inconsistent studies) [115]. Part II (treatment) brought together 23 adapted recommendations, 3 adopted and 8 new, with new evidence that was overall of low quality [149].

Loop colostomy is more prone to prolapse, and dilatations are painful in more than two thirds of cases, with distress for professionals and psychosocial trauma for parents and patients [149]. In Part IV (organisation of care), hospitals treating ARM should have access to a broad range of specialties, including clinical genetics (grade B); reference centres should treat at least 10 reconstructions per year (grade D, whereas the current eUROGEN criteria require at least 5); each patient should have a designated supervising physician and case manager for the whole pathway; the family doctor and regional paediatrician contact the centre when complications or admissions occur; and patient associations should organise at least one annual meeting, coordinated by the centre in their absence [150]. Referral to an experienced multidisciplinary centre improves continence outcomes [10], and higher volumes are associated with better surgical outcomes [150]. In an Amsterdam cohort of 41 patients with ARM and sacral agenesis, transanal irrigation was used by 22 of 33 patients aged 4 years or more, with faecal incontinence in 26.3% of users versus 71.4% of non-users, and 43.9% performed intermittent catheterisation; outcomes were associated with ARM complexity and not with the radiological severity of the sacral agenesis [181].

7.4. Heart disease

Screening echocardiography is recommended in all patients with possible VACTERL, because heart disease occurs in about two thirds and its severity is not predictable from the other components [121]. In ARM, the authors of the Egyptian cohort of 314 patients advocate universal echocardiography, and eUROGEN asks for heart disease to be excluded in the first 24 hours [123, 149]. Before any surgery, vascular anomalies should be delineated (Doppler, echocardiography, MR angiography in complex cases), and the ECG identifies arrhythmias that influence anaesthesia [19]. Surgical or transcatheter treatment follows the specific heart defect.

7.5. Kidney and urinary tract

The initial renal ultrasound is followed by micturating cystourethrography if there is obstruction, scarring or suspected VUR, by serial ultrasounds and by MAG3 scintigraphy with furosemide when indicated; infection prevention and management of VUR preserve renal function, and kidney transplantation may become necessary in severe forms [19, 129]. With a single kidney or reduced renal function, nephrotoxic drugs should be avoided, a GeneReviews recommendation in CNDD applicable by extension to any patient with reduced renal mass [40]. Renal assessment should continue throughout follow-up [129]. There are no consensus recommendations for renal surveillance specific to VACTERL; a 2026 editorial proposes risk-stratified surveillance, closer in complex renal anomalies, after stage 3 acute kidney injury or with repeated renal insults, with periodic estimated glomerular filtration rate (eGFR), albuminuria or proteinuria, blood pressure and review of nephrotoxic drugs according to the 2024 KDIGO guideline for CKD, as a conceptual framework and not as a validated protocol [130, 182]. In kidney transplantation, patients with VACTERL had more complications of peritoneal dialysis and lower graft function at 2 years than urological controls [131]. On urodynamics, eUROGEN recommends the examination in all patients with spinal dysraphism and in any child with strong suspicion of neurogenic bladder [142]. The case described in section 10.2 shows late urological complications after endoscopic injection of a non-absorbable agent, and the authors point out that the European paediatric urology guidelines prefer dextranomer/hyaluronic acid copolymer as the first-line endoscopic agent in VUR [183].

7.6. Spine and spinal cord

Early detection of tethered cord is beneficial, and MRI is more sensitive than ultrasound [19]. Patients with abnormalities on spinal ultrasound should be followed by paediatric neurology, and neurological deterioration or worsening continence during follow-up is an indication for assessment of tethered cord by neurology or neurosurgery [115]. Scoliosis may progress (Solomon 2011), and the GeneReviews on CNDD recommends monitoring it until skeletal maturity, a criterion applicable to congenital vertebral anomalies [10, 40]; back pain in adults may be refractory to laminectomy, medication and spinal cord stimulation [18].

7.7. Limbs

Early physiotherapy and surgery are indicated for limb defects [19]. In a patient with radial anomalies, the Oxford Desk Reference recommends considering occasional full blood counts [107]. FARF recommends referring the child with a limb anomaly to a paediatric hand and upper limb surgeon in the first months, testing for FA in all children with an isolated thumb or hand anomaly or with radial deficiency, starting stretching at every nappy change from birth and reserving pollicisation of the index finger for thumbs without a stable carpometacarpal joint; in the classification of radial deficiency (types 0–4), type 4 (complete absence of the radius) is the most frequent, and the distinction between types 3 and 4 can only be made at about 3 years of age [11].

7.8. Hydrocephalus

In VACTERL-H, transfontanellar ultrasound identifies hydrocephalus and shunting may improve outcomes [19]; in the Iafolla series, two of three infants survived after early neurosurgery [3].

7.9. Drugs

No medicinal product is indicated for the VACTERL association; a search of ClinicalTrials.gov in October 2026 found, with the terms for the association, a single interventional study (dumping syndrome after type III OA, NCT02525705, completed) and no drug study for VACTERL [23]. The drugs used are those for each component. ESPGHAN-NASPGHAN recommends PPIs as first line for GORD in OA, with acid suppression in all patients in the neonatal period and until the first year or longer, but does not specify the substance, dose or exact duration; doses follow the summary of product characteristics of each medicinal product and paediatric formularies, and prolonged use should be reassessed periodically [127]. Perioperative antibiotic therapy for oesophageal repair is consensual, but preoperative prophylaxis and extension beyond 24 hours postoperatively are not [147]. In recurrent strictures, ESPGHAN-NASPGHAN accepts intralesional or systemic corticosteroids and topical mitomycin C as adjuncts, without a fixed dose [127], but the ERNICA consensus did not approve them (46.2% and 26.7%) [155]; the only regimen cited in the sources for mitomycin C (0.1 mg/mL) comes from a retrospective study of 21 patients [127]. Intralesional injection of triamcinolone (10 mg/mL) before balloon dilatation is being studied in the STEPS-EA trial, without published results, and constitutes experimental off-label use [184, 185]. Glycopyrronium for anastomotic leak was studied in a randomised trial (8 μg/kg every 8 hours, a dose presented only as trial data), in off-label use, and the ERNICA consensus considered it premature to recommend it [147, 178]. Chronic macrolide use for bronchiectasis has not been studied in OA and is an extrapolation [140]. In the case described in section 10, granulocyte colony-stimulating factor (G-CSF) was used for neutropenia in Diamond-Blackfan anaemia, an indication belonging to that disease and not to VACTERL [96]. Niacin supplementation in pregnancy prevented malformations only in NAD-deficient mice, and in the Nadsyn1 model null mothers needed nicotinamide or nicotinamide mononucleotide; it has no indication or dosing regimen in humans [82, 83].

7.10. Regulatory status

The sources consulted did not include the FDA labels or the EMA summaries of product characteristics for PPIs in the neonatal age group, so the minimum authorised ages of each substance are not given.

7.11. Studies and trials

Component trials are few and small: in the ERNICA consensus, only 5 of 116 articles (4.3%) were level 1, abstracts rarely give confidence intervals, and two of them (Upadhyaya and Sharma) had their quality questioned by the panel [147]. The sources consulted did not identify trials, positive or negative, in the VACTERL population. There is no trial in a defined VACTERL population, and the results of trials in OA or ARM cannot be compared indirectly with one another or safely extrapolated to patients with multiple components, whose morbidity is greater [120, 147]. A negative search for trials does not prove that unregistered studies do not exist.

7.12. Developments in the last 12 months

7.13. Agents and procedures requiring caution, pregnancy, perioperative care and transition

The radiation and sedation of each examination should be weighed, especially for three-dimensional CT of the spine [19]. With a single kidney or reduced renal function, nephrotoxic drugs are avoided [40]. In FA, exposure to genotoxic agents follows the specific rules for Fanconi anaemia [14].

In the perioperative period, right aortic arch changes the surgical approach to OA [147], vascular and cardiac anomalies determine anaesthesia [19], and the cardiac malformation should be known before any repair [10]. Women with ARM should be followed during pregnancy by a gynaecologist experienced in ARM and have access to a paediatric surgeon; the perineum should be examined before conception and throughout pregnancy, the mode of delivery is individual and, in case of doubt, caesarean section should be strongly considered [115]. At the start of adolescence, boys and girls with ARM should receive information on sexuality, fertility and reproduction, and neonatal hydrocolpos may reduce fertility [115]; eUROGEN recommends a low threshold for preconception consultation, because fertility is reduced especially in cloaca and bladder neck fistula [142]. Primary prevention in women with pregestational diabetes rests on periconceptional glycaemic control, because the risk of malformation increases with HbA1c [104].

Transition to adult medicine should be to physicians experienced in OA (ESPGHAN-NASPGHAN, statement 34) and, in ARM, to a dedicated team that ensures lifelong follow-up (eUROGEN, Part III) [127, 142]. In ARM, eUROGEN recommends planning transition from 12–14 years and completing it before 18, with a personalised plan provided at the outset, a transition coordinator, joint paediatric and adult consultations and patient access to their clinical data [142]. In OA, the 2023 INoEA consensus (42 expert opinion statements) recommends a pulmonology consultation and lung function tests at transition and then, on an individual basis, annually; dietitian and swallowing therapist consultation for all adolescents at transition and, ideally, annually in adults, with attention to iron, zinc, vitamins B12, A and C, folate and fibre; assessment of quality of life before transfer; and a low threshold for airway endoscopy when symptoms persist, especially with long-gap OA or congenital heart disease [140]. After oesophageal replacement, endoscopic and respiratory follow-up should be closer, and laparoscopic fundoplication is the surgical approach for refractory GORD in adults, after the disease has been confirmed by 24-hour pH-impedance [140]. Adults with VACTERL tend not to be followed up, and Raam and colleagues recommend a uniform assessment and a low threshold for investigating sequelae [18].

7.14. Guideline recommendations and divergences

8. Reproductive Options and Family Counselling

8.1. Recurrence risk in VACTERL without an identified cause

About 90% of cases are sporadic, and the recurrence risk is low once FA, Feingold syndrome, Holt-Oram syndrome, Townes-Brocks syndrome and VACTERL-H have been excluded, and should be adjusted to the family history [10, 143]. Empirical estimates vary: about 1% for siblings and offspring according to the GeneReviews on Townes-Brocks, and 2–3% according to the Oxford Desk Reference [144, 190, 191]. Familial recurrence is rare: in a review of 12 published familial cases, in only two did both affected relatives meet full criteria [192]; Nezarati and McLeod described a mother and son with VACTERL, the first report of transmission to offspring, and Auchterlonie and White two siblings [1].

Data on first-degree relatives diverge. Solomon and colleagues, in 78 NIH probands, found 7 (9%) with a first-degree relative with at least one component and, in families with detailed data, 4 of 141 relatives (5.0%) with a major component, mainly vertebral, a figure higher than in the general population [1, 193]. Bartels and colleagues, in 87 German patients and 271 first-degree relatives, found no overall increase (p=0.10); OA/TOF was more frequent in relatives (OR 17.65; 95% CI 2.47–126.05), but because of a single family, and the authors considered the risk very low, while being unable to study the offspring of patients who were still young [194]. The divergence may reflect different ascertainment (genetics clinic in the USA, surgical network in Germany), and the offspring of patients themselves remain little studied.

Possible mechanisms of recurrence in undiagnosed forms include de novo dominant variants, unrecognised or private recessive variants, multifactorial inheritance and non-genetic causes (stochastic, epigenetic, teratogenic) [12]. Concordance in monozygotic twins is low (5–20%), and twin concordance in OA/TOF was about 2.5% [12, 109]. In monozygotic twins, counselling should cover the twinning and the malformation together; the recurrence risk is considered low to negligible, and the co-twin may have lesser degrees of the same defect [109].

8.2. Cascade testing and carriers

When a cause is identified, testing of the parents defines the risk. In FA due to FANCB, female carriers are not detected by the breakage test and require molecular testing, and maternal gonadal mosaicism is possible if the variant is not found in the mother's blood [8, 14]. In the Holden family, identification of FANCB was relevant for counselling in isolated male cases of VACTERL-H [52]. In autosomal dominant forms, a parent may have a minimal phenotype: in the van de Putte series, the mother of a patient with a SALL4 variant had only a short thumb, and in the RPL18 family the grandmother and mother had subtle vertebral and thumb anomalies and mild neutropenia [57, 96]. In undiagnosed forms, clinical examination and, when indicated, renal and vertebral imaging of the parents may identify subtle components [10]. Siblings of a patient with FA should be tested because of the haematological risk and possible haematopoietic stem cell donation; FARF recommends breakage testing in all full siblings and, in FA due to FANCB, in brothers (breakage or familial variant), and notes that maternal female relatives are more likely to be carriers [11, 14]. The known founder effects in FA (Afrikaners and FANCA, Amish and FANCE, Ashkenazi Jews and BRCA2 or FANCC, South Asians and FANCL, Japanese and FANCC or FANCG, Spanish and Portuguese Roma and FANCA) concern autosomal genes and not FANCB [8, 14, 68]. Carriers of variants in BRCA1, BRCA2, PALB2, BRIP1 or RAD51C have their own cancer risks, managed according to National Comprehensive Cancer Network guidelines [11]. In CNDD, the genetic status of asymptomatic siblings should be assessed in order to look for occult malformations [40].

8.3. Prenatal and preimplantation diagnosis

With a known familial pathogenic variant, prenatal diagnosis by chorionic villus sampling or amniocentesis and preimplantation genetic diagnosis (PGD) are possible [12, 14, 40]. In FA, prenatal diagnosis can be made by breakage studies or by the variant, and PGD with HLA typing has, in the autosomal recessive form, a theoretical probability of 18.75% (3/16) per embryo of being unaffected and HLA-identical, so many couples need several cycles; confirmatory prenatal diagnosis is recommended in pregnancies obtained by IVF with PGD [11]. Without an identified cause, surveillance of a subsequent pregnancy rests on a detailed anomaly scan between 18 and 22 weeks, recommended by eUROGEN when the risk of anomalies is increased, and on fetal echocardiography according to the previous finding [115]. Ultrasound does not reliably detect OA and ARM [12, 115]. Storing DNA from the proband without a molecular diagnosis allows future reanalysis and targeted testing [12]. In women with pregestational diabetes, periconceptional glycaemic control reduces the risk of malformations [104].

8.4. Modifiable factors and assisted reproduction

Counselling on IVF should present the relative increase (aOR 1.86) together with the absolute risk: 2.3 per 10,000 live births after IVF versus 1.2 per 10,000 with natural conception, in the American registries [16]. In the European OA registry, MAR was not associated with more VACTERL [106]. Maternal obesity and smoking have been mentioned as risk factors, without specific estimates in the sources consulted [55].

8.5. Counselling of minors and the family

Carrier testing for FANCB or ZIC3 in asymptomatic girls has no medical benefit in childhood and should be discussed when they are able to decide, in line with general practice in the genetic counselling of minors. Counselling should explain that VACTERL is a diagnosis of exclusion, which may be revised with new tests, and that cognitive function is usually normal [2, 10]. In adolescence, patients with ARM should receive information on sexuality, fertility and reproduction [115]. Patient associations have a role recognised by the European consensus statements [155].

9. Special Considerations: Population Diversity and Epidemiology

9.1. Prevalence and what each figure measures

The differences reflect definitions (three of five or of six components, inclusion of heart defects, exclusion of syndromes and chromosomal anomalies), the inclusion of terminations and fetal deaths and the type of surveillance [10, 15]. Registries tend to overestimate, because they do not exclude similar conditions or perform FA testing or microarray, and clinical series tend to underestimate [10]. The GOBACK estimate is a ratio calculated from registries and not a US national prevalence [110]. For comparison, EUROCAT records over the same period 2.68/10,000 for OA with or without TOF, 3.45/10,000 for anorectal atresia or stenosis and 1.24/10,000 for preaxial longitudinal limb defects [15]. The Finnish cohort recorded 8.00 ARMs per 10,000 births [120]. The Orphanet prevalence (6.25/100,000) is sourced from Solomon's 2011 review and expert opinion, and the worldwide point prevalence is recorded as unknown and not validated [5].

9.2. Geography, ancestry and founder effect

There is no strong evidence of higher regional or ethnic incidence [10]. In the American GOBACK cohort, 37.8% of mothers were Hispanic, versus 24.4% in children without defects, an observation that the authors do not interpret as a causal effect [110]. The combinations of components vary between continents, with a cardiac-renal-anal predominance in the USA [16]. The TRAP1 variant p.(Arg469His) was proposed in 2014 as a European founder variant, but is now classified as benign or likely benign, and does not constitute a founder effect for VACTERL [37, 80]. EUROCAT stopped publishing prevalence by registry for data protection reasons, and the sources consulted do not include separate prevalences for Portugal or Brazil; the Brazilian textbook consulted does not present its own epidemiological data [15, 49]. The Portuguese congenital anomalies registry of the National Health Institute Doutor Ricardo Jorge (INSA) took part in the van de Putte EUROCAT study [17]. The Portuguese national FA cohort (93 cases, 1993–2025) had 39% of patients of Roma ethnicity, consanguinity in 41% (92% of these in the Roma community) and 35 homozygotes for the Iberian Roma founder variant NM_000135.4:c.295C>T p.(Gln99Ter) of FANCA, the same one described in Spanish Roma families, and VACTERL-H in 7% [14, 68]. In Brazil, a national multicentre study of the outcome of newborns with OA is registered (NCT07210736, Hospital das Clínicas of the University of São Paulo, 72 centres, 1,000 patients planned between 2025 and 2027), still without results [23]; the Brazilian study by Quirino and colleagues (2012), cited by the Oxford Desk Reference with regard to renal survival, concerns CAKUT in general and not VACTERL [132]. The carrier frequency for FA of any gene is 1:181 in the USA and 1:93 in Israel [11]. The lack of data in these sources does not prove that no published studies exist.

9.3. Special populations

Monozygotic twins have an excess of VACTERL with discordance in most cases [50, 109]; in the EUROCAT series, 6% of cases were twins, 18% of mothers were aged 35 years or more, 44% of live births were preterm and 51% had low birth weight [17]. IVF pregnancies have an increased relative risk [16]. Children of mothers with pregestational diabetes have an increased risk, proportional to periconceptional HbA1c [104]. Preterm and very low birth weight newborns with ARM and VACTERL account for most of the neonatal mortality [120]. Adults form a population with insufficient follow-up [18]. In consanguineous families, the probability of FA, CNDD and other autosomal recessive forms increases [40, 107].

9.4. European Reference Networks and patient associations

The relevant ERNs are ERNICA (congenital digestive anomalies, including OA and ARM), ERN eUROGEN (anorectal and urogenital malformations; 56 providers in 20 countries and about 12,500 patients per year), ERN ITHACA (congenital malformations and syndromes), ERKNet (kidney diseases), ERN EuroBloodNet (rare haematological diseases, when FA is confirmed) and, if skeletal dysplasia is in the differential, ERN BOND [24–28, 142, 195]. EURORDIS represents European rare disease patient associations [196]. Active patient associations verified in October 2026 include the VACTERL Network, aimed at families of children and at adults with VACTERL/VATER, with a parent network and crisis support [197]; the Pull-thru Network (USA), for anorectal malformations and associated conditions [198]; SoMA e.V. (Germany), for anorectal malformations, Hirschsprung disease and cloacal exstrophy [199]; and TOFS (United Kingdom), the international federation EAT and KEKS e.V. (Germany), for OA and TOF [200–202]. AIMAR (Italy) supports patients with ARM and, with SoMA e.V., represented patients on the eUROGEN guideline panel, which also recommends the material on sexuality in ARM and Hirschsprung disease available at sexuality-arm-hd.com [115, 142, 203]. Reach (United Kingdom) supports families with upper limb defects [107]. For FA, the Fanconi Anemia Research Fund (USA), which publishes the clinical guidelines and a Portuguese translation, the Deutsche Fanconi-Anämie-Hilfe (Germany) and Fanconi Hope (United Kingdom, a registered charity that maintains the UK FA registry) are active [11, 204, 205]. eUROGEN recommends that patient associations organise at least one annual meeting and that, in the absence of a national association, international associations be indicated [149, 150].

10. Illustrative Clinical Case

10.1. A «familial VACTERL» reclassified as Diamond-Blackfan anaemia

Leshchynska and colleagues published in 2026 a three-generation family, followed in the USA (Greenwood, South Carolina) and Australia (Sydney), referred with suspected familial VACTERL [96]. The male proband had vertebral and rib anomalies (Klippel-Feil and Sprengel deformity), ASD, coarctation of the aorta, absent right kidney, absent right thumb, duplicated left thumb, congenital hypothyroidism, fetal growth restriction and subsequent short stature [96]. The mother had a bifid thumb, supernumerary vertebrae, a fused coccyx and a height of 150 cm; the maternal grandmother had Klippel-Feil syndrome with cervical fusions and Sprengel deformity; a maternal aunt had a supernumerary cervical vertebra, and a deceased maternal uncle had a bifid thumb and had died of pulmonary haemorrhage; three relatives had Hashimoto's thyroiditis [96].

The haematological course was decisive. The proband had intermittent leucopenia and moderate to severe neutropenia from 12 months of age, attributed to viral infections, and was only referred to haematology at 30 months; he had repeated normocytic anaemia from 30 months to 6 years, with two transfusions for haemoglobin below 70 g/L and spontaneous resolution after 6 years, and received G-CSF once or twice a week from 3 to 6 years and, thereafter, intermittently for febrile neutropenia [96]. At 15 years, the bone marrow had 30–40% cellularity, erythroid predominance without dysplasia, a 46,XY karyotype and a myeloid/erythroid ratio of 0.4:1, consistent with ineffective erythropoiesis; in peripheral blood, leucocytes were 1.7×10⁹/L, neutrophils 0.41×10⁹/L, haemoglobin 152 g/L, mean corpuscular volume 83.6 fL, platelets 181×10⁹/L, reticulocytes 1.44%, erythropoietin 17.0 mU/mL, erythrocyte adenosine deaminase 567 mU/g of haemoglobin (normal 400–900) and fetal haemoglobin below 1.0% [96]. The grandmother, mother, an aunt and a cousin had mild to moderate leucopenia and neutropenia without acute illness [96].

Genome sequencing in five family members identified in the proband the heterozygous variant NM_000979.4:c.397G>C p.(Gly133Arg) of RPL18 (NC_000019.10:g.48616103C>G), inherited from the mother, novel, present in all affected members, in a haploinsufficient gene associated with Diamond-Blackfan anaemia 18 (OMIM 618310); an RPS6 variant, considered probably not damaging because it was present in the unaffected grandfather and in 33 individuals in gnomAD, and an IDUA variant were also found [96]. In functional studies, the mutant protein lost about 95% of its quantity after 6–8 hours of cycloheximide, versus 2% for the reference protein, and reduced protein synthesis [96]. The only previously described family with an RPL18 variant had anaemia and neutropenia without congenital anomalies [96]. Figure 1 of the article shows the pedigree (proband III.3; genome in III.3, III.4, II.1, II.2 and I.2) and the Sanger electropherograms of the RPL18 and RPS6 variants (https://pmc.ncbi.nlm.nih.gov/articles/PMC13172565/figure/Fig1/); the caption was read and the image was not visually inspected [96].

The case shows that familial VACTERL components, with expressivity ranging from a single defect to multiple defects, may correspond to an autosomal dominant ribosomopathy, and that mild and persistent cytopenias are a red flag [96]. The PanelApp VACTERL panel does not include RPL18, and the authors advocate unrestricted genomic sequencing [78, 96]. The haematological management described (G-CSF) is that of the underlying disease and not a VACTERL routine. The case also reinforces the recommendation of a full blood count with film in the initial assessment [19, 21].

10.2. Late urological complications in an adolescent with VACTERL

Escolino and colleagues (Naples, 2025) described a boy with VACTERL from birth, operated on in the first year for OA with TOF and tetralogy of Fallot, with a lumbosacral lipoma and tethered cord (untethering between 1 and 2 years, normal postoperative MRI), Y-type urethral duplication with a hypospadiac orthotopic urethra (excision of the accessory urethra and urethroplasty at 2 years) and high-grade bilateral VUR, treated with bilateral Cohen ureteral reimplantation at 1 year and, because of recurrence, with two endoscopic injections of polydimethylsiloxane (Macroplastique®) between 1 and 3 years [183]. He had no urological follow-up from 3 to 15 years [183].

At 15–16 years he presented with recurrent febrile UTIs, three episodes of orchiepididymitis, lumbar pain and a weak stream with abdominal straining; uroflowmetry showed a mean flow of 18.52 mL/s, a voiding time of 61.32 s and a volume of 950 mL, ultrasound bilateral hydronephrosis with megaureter, a thickened bladder wall, a 2-cm hyperechoic nodule at the left ureterovesical junction and a residual volume above 60%, creatinine was 1.4 mg/dL, and MAG3 scintigraphy showed left relative function of 35.5% with a half-time of emptying above 25 minutes [183]. An alpha-blocker, double voiding and intermittent catheterisation twice a day did not improve the picture (poor adherence); lumbosacral MRI showed no spinal cord abnormalities, and urodynamics revealed a hypotonic, hyporeflexic bladder (capacity 1,002 mL, maximum detrusor pressure 8.4 cmH2O, residual volume 350 mL) [183]. At surgery there was periureteral and trigonal fibrosis; bilateral Politano-Leadbetter ureteral reimplantation, calibration of the bladder neck to 26 F (without organic stenosis) and limited reduction cystoplasty were performed, and histology showed a foreign-body granulomatous reaction to non-absorbable particles [183]. Creatinine fell to 0.9 mg/dL, left relative function rose to 41% with a half-time of emptying below 10 minutes, maximum flow was 22.5 mL/s with a residual volume below 50 mL at 3 months, and the patient was asymptomatic and voiding normally at 3 years of follow-up [183].

The authors conclude that, in VACTERL with urinary anomalies and early reconstructions, late iatrogenic complications may arise atypically and require prolonged renal and bladder surveillance, and advise against non-absorbable bulking agents in children [183]. The interruption of follow-up between 3 and 15 years runs counter to the recommendation of structured lifelong follow-up in the component guidelines, and the management described is not presented as routine [142]. The figures of the article are at https://pmc.ncbi.nlm.nih.gov/articles/PMC12643402/figure/reports-08-00239-f001/ (retrograde pyelography), https://pmc.ncbi.nlm.nih.gov/articles/PMC12643402/figure/reports-08-00239-f002/ (urodynamics), https://pmc.ncbi.nlm.nih.gov/articles/PMC12643402/figure/reports-08-00239-f003/ (histology) and https://pmc.ncbi.nlm.nih.gov/articles/PMC12643402/figure/reports-08-00239-f004/ (ultrasound before and after surgery); the links were obtained from the article page [183].

10.3. A family with X-linked VACTERL-H due to FANCB

Holden and colleagues (2006) studied a three-generation British family [52]. Fetus III-1, terminated at 20 weeks (240 g), had abnormal cervical vertebrae C2–C6, bilateral absence of thumbs and radii, left renal agenesis, bilateral ventriculomegaly with a patent aqueduct, incomplete lung lobulation, single umbilical artery, undescended testes and growth restriction; the karyotype was 46,XY, and fibroblasts showed increased breakage with DEB (0.56 and 0.54 breaks per cell, versus 0.44–1.25 in affected individuals and 0.00–0.20 in controls) [52]. The maternal uncle II-2, stillborn at 30 weeks (1,038 g), had hydrocephalus with Arnold-Chiari malformation, absent thumbs and radii, right renal agenesis and left renal dysplasia, ASD, VSD, coarctation, OA with TOF, abnormal ears and L5/S1 spina bifida occulta [52]. The variant, now NM_001018113.3:c.1496+5G>A, causes skipping of exon 7; the female carriers had 100% skewed X inactivation and had no phenotype or cancer (ages 12 to 49 years) [52, 70]. Figure 1 of the article (pedigree, radiograph of the fetus with bilateral absence of radii and thumbs and cervical anomalies, X inactivation and sequence) is at https://pmc.ncbi.nlm.nih.gov/articles/PMC2564576/figure/fig1/ and Figure 2 (RT-PCR with exon 7 skipping) at https://pmc.ncbi.nlm.nih.gov/articles/PMC2564576/figure/fig2/; the links were obtained from the article page [52]. The case illustrates the value of breakage testing in isolated male cases of VACTERL-H and of studying X inactivation in the mother for counselling [52].

10.4. The original patient of Quan and Smith

The infant described by Quan and Smith had vertebral anomalies, anal atresia, OA with TOF, left radial aplasia and hypoplasia of the right thumb, and at 2 years had normal intelligence; Figure 1 of the Smith's chapter shows this patient (1A in the neonatal period and 1B at 2 years) and, in 1C, a diagram of the frequencies of the target defect when ascertainment starts from another defect, and Figure 2 depicts extended VACTERL schematically, with a right hand with a severe radial defect and a left hand with subtle thenar hypoplasia [44, 206]. Read from the image, the diagram gives, from TOF, 23% vertebral defects, 10% imperforate anus and 7% radial dysplasia; from imperforate anus, 36%, 7% (TOF) and 5% (radial dysplasia); and from radial dysplasia, 27% (vertebral), 3% (TOF) and 3% (imperforate anus), without denominators [44].

11. Prognosis and Long-Term Follow-Up

11.1. Prognosis

The prognosis depends on the malformations and their correction, and most children have normal or near-normal cognitive development [2, 107, 143]. In the Kansas City series of 112 patients with OA (1985–2005), overall survival was 92.9%, and VACTERL anomalies had little impact on survival [116]. In the Finnish cohort of 646 ARMs (2004–2017), neonatal mortality was 4.6% and infant mortality 6.0%, associated with very low birth weight, prematurity, heart disease and VACTERL (p=0.0002 and p<0.001), whereas postnatal survival with isolated ARM was 100% [120]. In the EUROCAT series, 87% of live births survived more than one week, with a difference between the «VACTERL-like» (96%) and «VACTERL-plus» (77%; p=0.002) subgroups, and terminations of pregnancy were 7% and 27%, respectively [17]. In the Spanish OA cohort, mortality was 11.4%, all in patients with complex malformations or extreme prematurity [126]; according to FARF, newborns with OA/TOF weighing more than 1,500 g and without major heart disease have 98% survival [11]. These figures describe treated cohorts of components and not the natural history of untreated VACTERL, which the sources do not describe. The prognosis is unfavourable when the components are part of a chromosomal picture such as trisomy 18 or del(13q) [2]. In VACTERL-H, a poor prognosis is the rule, with survival and a good outcome in some patients treated with early neurosurgery [2, 3]; in the FANCB cases of the McCauley series, only three of six survived the perinatal period [20]. In FA with a VATER phenotype, median survival is shorter and neoplasms appear earlier than in other FA [29]. In ACDMPV, mean survival without lung transplantation is about 7 months; in the review of 165 patients published between 2018 and 2025 (with publication bias), 45 received extracorporeal membrane oxygenation (ECMO) and the 10 transplanted patients had a mean survival of about 81 months, and the diagnosis requires genetic or histological confirmation, bearing in mind that histology may fail because of the mosaic distribution [31]. In CNDD, life expectancy is unknown; of the nine deaths described, five were fetal and four in the first year, and the oldest living patient was 30 years old [40]. In FA, Smith's reports a mean life expectancy of 20 years, and in FA due to BRCA2 intron 7 splicing variants all patients developed acute myeloid leukaemia by 3 years of age [9, 14]. In heterotaxy of all causes, first-year mortality was 30.9%, and the main determinant is the heart defect [30].

In adulthood, the dominant sequelae are back pain (55% of the NIH adults), dysphagia and reflux (45%), reactive airway disease (27%), UTIs and urolithiasis (45%) and constipation, and renal function was reduced in 9% [18]. After OA, dysphagia and GORD persist into adulthood, oesophagitis and gastric and intestinal metaplasia (Barrett's) are more frequent than in the general population, and ESPGHAN-NASPGHAN found no demonstrated increase in oesophageal cancer, although it remains a concern [127]. INoEA subsequently estimated Barrett's in 5.0% of patients followed in the long term and brought together 14 oesophageal cancers in adults with OA, with a median age of 44 years; in one study, the 10-year prevalence of squamous cell carcinoma in adults with OA under screening was 0.7%, about 100 times that of the general population, but the true prevalence is unknown because few patients have been followed into adulthood [140]. In the Rotterdam cohort, Barrett's was present in 7% of the 271 adults, and the youngest with clinically relevant Barrett's was 20.9 years old [141]. Overall quality of life was not shown to be reduced in children and adults with OA compared with the general population, and the guideline recommends prolonged medical and psychosocial support [127]. In ARM, continence is better in perineal and rectovestibular fistulas, and sexual and psychosocial problems are frequent [180]; patients with ARM have a higher risk of developmental or intellectual disorder, anxiety, depression and hyperactivity, and eUROGEN acknowledges a possibly increased risk of colorectal cancer in young adults, without evidence for specific screening [142]. In VACTERL, CKD (stages 2–5) affected 14.9% of a Korean paediatric cohort, and in an American series two thirds of patients with CKD reached end-stage kidney disease [130, 131]. The risk of childhood cancer is increased (HR 3.0) but the absolute risk is low (8 cancers in 2,288 children with a median follow-up of 7.9 years), and there is no recommended cancer screening protocol [110].

11.2. Surveillance

There is no VACTERL-specific surveillance guideline; the intervals come from the component guidelines and expert proposals, and, when a source does not define the interval, the table says so [19, 115, 127].

11.3. Organisation of follow-up

Follow-up should be interdisciplinary and centralised, with involvement of patient associations, according to the ERNICA and eUROGEN consensus statements [142, 150, 155]. ERNICA unanimously approved a structured lifelong follow-up schedule and an interdisciplinary programme with a coordinating specialist [155]. eUROGEN recommends seeing all children and young adults with ARM at the reference centre at key ages, in a programme led by the paediatric surgeon with a nurse case manager, monitoring digestive and urogenital function (grade B), assessing the scar and quality of life, and does not recommend routine anorectal manometry; the Holschneider and Rintala questionnaires are not validated for bowel follow-up [142]. The structured schedule of the Dutch standard on which eUROGEN is based (Table 3.1 of the supplement) was not consulted, and the guideline does not set numerical intervals [142]. The diagnosis of exclusion should be reviewed during follow-up, because new clues (cytopenias, cognitive deficit, new components) or new genomic technologies may lead to reclassification [10, 96]. In adults, a low threshold for investigating anomalies not identified in childhood is justified by the proportion of malformations discovered late [18].

12. Summary and Final Considerations

The VACTERL association describes the non-random co-occurrence of at least three vertebral, anorectal, cardiac, tracheo-oesophageal, renal and limb anomalies, without an alternative diagnosis. It is not a disease with a single cause, but a category of exclusion that brings together different mechanisms, from monogenic and chromosomal phenocopies to early embryonic disturbances, with a probable role for maternal factors such as pregestational diabetes and, to a lesser extent, in vitro fertilisation. In Europe, the birth prevalence is around 0.5 per 10,000 births, including terminations of pregnancy, and the figures vary with the definition and the type of registry.

Recognition starts from one component, usually oesophageal atresia or anorectal malformation, and requires a systematic search for the others by vertebral radiography, spinal ultrasound in the first month, echocardiography with electrocardiogram, renal ultrasound, limb examination and transfontanellar ultrasound. The aetiological work-up includes a full blood count, a chromosome breakage study with diepoxybutane in all patients and exome or genome sequencing with copy number variant analysis, or microarray when these are not available. The genomic yield is low in patients meeting strict criteria and higher when there is neurocognitive deficit, dysmorphism or defects outside the acronym, which act as red flags. Fanconi anaemia, VACTERL-H due to FANCB or ZIC3, alveolar capillary dysplasia due to FOXF1, congenital NAD deficiency, Townes-Brocks, Feingold, Holt-Oram, CHARGE and 22q11.2 deletion syndromes and the ribosomopathies are the differentials with the greatest practical consequence. The evidence associating TRAP1 and a ZIC3 variant with the classic form has weakened with the reclassification of the original variants as benign, the HOXD13 variant described in one patient has become of uncertain significance, and the relationship with PTEN rests on a single patient, whose variant is likely pathogenic for PTEN hamartoma tumour syndrome but has no confirmed link to VACTERL. Between 5% and 30% of patients with Fanconi anaemia meet the criteria for VACTERL-H, a proportion that was 7% in the Portuguese national cohort, dominated by FANCA, and up to 40% of patients with Fanconi anaemia have no physical anomalies.

Treatment is surgical and multidisciplinary, component by component, supported by European and American consensus statements on oesophageal atresia (ERNICA, ESPGHAN-NASPGHAN, INoEA) and anorectal malformation (eUROGEN, APSA) with evidence mainly from expert opinion, which diverge on specific points such as the endoscopic schedule, the duration of antacid therapy, adjuncts in recurrent stricture and the minimum caseload of centres; there are no authorised drugs or interventional trials for the association. Cognitive function is usually normal, but morbidity persists into adulthood (back pain, dysphagia, reflux, Barrett's oesophagus, constipation, urinary tract infections, urolithiasis and chronic kidney disease), and some malformations are only recognised late, which justifies lifelong follow-up and structured transition. The recurrence risk is low when Mendelian causes have been excluded, and identification of a cause changes counselling, testing of relatives and the options for prenatal and preimplantation diagnosis. The methylation episignature common to recurrent constellations of embryonic malformations and population-based studies on cancer and assisted reproduction are the most recent lines of research.

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